Updated on 2022/10/01

写真a

 
HIROHATA Satoshi
 
Organization
Faculty of Health Sciences Professor
Position
Professor
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Degree

  • 博士(医学) ( 岡山大学 )

Research Interests

  • MMP

  • ADAMTS

  • Extracellular matrix

Research Areas

  • Life Science / Biomedical engineering

  • Life Science / Cardiology

  • Others / Others  / Laboratory medicine

  • Life Science / Biomaterials

  • Life Science / Orthopedics

  • Life Science / Pathological biochemistry

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Education

  • Okayama University   医学研究科  

    - 1997

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    Country: Japan

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  • Okayama University    

    - 1992

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  • Okayama University   医学部  

    - 1992

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    Country: Japan

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Research History

  • - 岡山大学保健学研究科 教授

    2014

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  • - Professor,Graduate School of Health Sciences,Okayama University

    2014

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  • Okayama University   Center for Global Partnerships and Education

    2012 - 2014

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  • Associate Professor,Center for Global Partnerships and Education,Okayama University

    2012 - 2014

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  • Assistant Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2004 - 2012

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  • 岡山大学医歯薬学総合研究科 助教

    2004 - 2012

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  • postdoctoral fellow,Cleveland Clinic Foundation Lerner Research Institute

    1997 - 2000

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  • クリーブランドクリニック ラーナー研究所 博士研究員

    1997 - 2000

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Professional Memberships

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Committee Memberships

  • 日本動脈硬化学会   専門医  

    2014.7   

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  • 日本循環器学会   演題査読員  

    2007 - 2017   

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    Committee type:Academic society

    日本循環器学会

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  • 日本循環器学会   専門医  

    2004.4   

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  • 日本結合組織学会   評議員  

    2002   

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    Committee type:Academic society

    日本結合組織学会

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  • 日本内科学会   総合内科専門医  

    2000   

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    Committee type:Academic society

    日本内科学会

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Papers

  • Suppression of nitric oxide synthase aggravates non-alcoholic steatohepatitis and atherosclerosis in SHRSP5/Dmcr rat via acceleration of abnormal lipid metabolism. Reviewed International journal

    Ikumi Sato, Shusei Yamamoto, Mai Kakimoto, Moe Fujii, Koki Honma, Shota Kumazaki, Mami Matsui, Hinako Nakayama, Sora Kirihara, Shang Ran, Shinichi Usui, Ryoko Shinohata, Kazuya Kitamori, Satoshi Hirohata, Shogo Watanabe

    Pharmacological reports : PR   2022.7

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    BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a progressive subtype of non-alcoholic fatty liver disease (NAFLD) that is closely related to cardiovascular disease (CVD). Nitric oxide (NO) plays a critical role in the control of various biological processes. Dysfunction of the NO signaling pathway is associated with various diseases such as atherosclerosis, vascular inflammatory disease, and diabetes. Recently, it has been reported that NO is related to lipid and cholesterol metabolism. Chronic NO synthase (NOS) inhibition accelerates NAFLD by increasing hepatic lipid deposition. However, the detailed relationship between NO and abnormal lipid and cholesterol metabolism in NAFLD/NASH has not been completely explained. We aimed to determine the effects of NOS inhibition by N omega-nitro-L-arginine methyl ester hydrochloride (L-NAME), a NOS inhibitor, on NASH and CVD via lipid and cholesterol metabolism. METHODS: Stroke-prone spontaneously hypertensive rats were fed a high-fat and high-cholesterol diet for 8 weeks and administered L-NAME for the last 2 weeks. Following blood and tissue sampling, biochemical analysis, histopathological staining, quantitative RT-PCR analysis, and western blotting were performed. RESULTS: L-NAME markedly increased hepatic triglyceride (TG) and cholesterol levels by promoting TG synthesis and cholesterol absorption from the diet. L-NAME increased the mRNA levels of inflammatory markers and fibrotic areas in the liver. Cholesterol secretion from the liver was promoted in rats administered L-NAME, which increased serum cholesterol. L-NAME significantly increased the level of oxidative stress marker and lipid deposition in the arteries. CONCLUSIONS: NOS inhibition simultaneously aggravates NASH and atherosclerosis via hepatic lipid and cholesterol metabolism.

    DOI: 10.1007/s43440-022-00380-1

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  • A high-fat/high-cholesterol diet, but not high-cholesterol alone, increases free cholesterol and apoE-rich HDL serum levels in rats and upregulates hepatic ABCA1 expression. Reviewed International journal

    Ryoko Shinohata, Misako Shibakura, Yujiro Arao, Shogo Watanabe, Satoshi Hirohata, Shinichi Usui

    Biochimie   197   49 - 58   2022.6

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    A high-fat/high-cholesterol (HFC) diet, but not a high-cholesterol (HC) diet, is known to induce elevated serum apolipoprotein E (apoE)-rich high-density lipoprotein (HDL) levels in animal models. However, the exact mechanisms by which the combination of dietary fat and cholesterol induces apoE-rich HDL production is not well understood. Here, we investigated the effects of dietary fat and cholesterol on serum lipoprotein profiles and hepatic mRNA expression that are associated with HDL production, cholesterol transport, and bile acid metabolism. Male Sprague-Dawley rats were fed HFC, HC, high-fat, or control diets and then evaluated. The HFC diet induced significant increases in hepatic free-cholesterol accumulation (1.4-fold, p < 0.01) and serum apoE-rich HDL cholesterol (8.7-fold, p < 0.001) levels compared with the HC diet. The apoE-rich HDL induced by the HFC diet was remarkably rich in free cholesterol. Liver gene-expression was mostly similar between the HC and HFC diet groups. However, there was a significant increase of ATP-binding cassette transporter A1 (ABCA1) levels in the HFC group compared to the HC group for both mRNA (1.9-fold, p < 0.001) and protein (6.6-fold, p < 0.01). These results suggest that an increase in apoE-rich HDL induced by dietary fat and cholesterol may be involved in cholesterol efflux from the liver through increased ABCA1-mediated free-cholesterol efflux.

    DOI: 10.1016/j.biochi.2022.01.011

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  • Potential of a Novel Chemical Compound Targeting Matrix Metalloprotease-13 for Early Osteoarthritis: An In Vitro Study. Reviewed International journal

    Junko Inagaki, Airi Nakano, Omer Faruk Hatipoglu, Yuka Ooka, Yurina Tani, Akane Miki, Kentaro Ikemura, Gabriel Opoku, Ryosuke Ando, Shintaro Kodama, Takashi Ohtsuki, Hirosuke Yamaji, Shusei Yamamoto, Eri Katsuyama, Shogo Watanabe, Satoshi Hirohata

    International journal of molecular sciences   23 ( 5 )   2022.2

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    Osteoarthritis is a progressive disease characterized by cartilage destruction in the joints. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) play key roles in osteoarthritis progression. In this study, we screened a chemical compound library to identify new drug candidates that target MMP and ADAMTS using a cytokine-stimulated OUMS-27 chondrosarcoma cells. By screening PCR-based mRNA expression, we selected 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide as a potential candidate. We found that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated IL-1β-induced MMP13 mRNA expression in a dose-dependent manner, without causing serious cytotoxicity. Signaling pathway analysis revealed that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated ERK- and p-38-phosphorylation as well as JNK phosphorylation. We then examined the additive effect of 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide in combination with low-dose betamethasone on IL-1β-stimulated cells. Combined treatment with 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide and betamethasone significantly attenuated MMP13 and ADAMTS9 mRNA expression. In conclusion, we identified a potential compound of interest that may help attenuate matrix-degrading enzymes in the early osteoarthritis-affected joints.

    DOI: 10.3390/ijms23052681

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  • Osteopontin silencing attenuates bleomycin-induced murine pulmonary fibrosis by regulating epithelial–mesenchymal transition Reviewed International journal

    Omer Faruk Hatipoglu, Eyyup Uctepe, Gabriel Opoku, Hidenori Wake, Kentaro Ikemura, Takashi Ohtsuki, Junko Inagaki, Mehmet Gunduz, Esra Gunduz, Shogo Watanabe, Takashi Nishinaka, Hideo Takahashi, Satoshi Hirohata

    Biomedicine & Pharmacotherapy   139   111633 - 111633   2021.7

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    Idiopathic pulmonary fibrosis (IPF) is the most common and most deadly form of interstitial lung disease. Osteopontin (OPN), a matricellular protein with proinflammatory and profibrotic properties, plays a major role in several fibrotic diseases, including IPF; OPN is highly upregulated in patients' lung samples. In this study, we knocked down OPN in a bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model using small interfering RNA (siRNA) to determine whether the use of OPN siRNA is an effective therapeutic strategy for IPF. We found that fibrosing areas were significantly smaller in specimens from OPN siRNA-treated mice. The number of alveolar macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage fluid was also reduced in OPN siRNA-treated mice. Regarding the expression of epithelial-mesenchymal transition (EMT)-related proteins, the administration of OPN-siRNA to BLM-treated mice upregulated E-cadherin expression and downregulated vimentin expression. Moreover, in vitro, we incubated the human alveolar adenocarcinoma cell line A549 with transforming growth factor (TGF)-β1 and subsequently transfected the cells with OPN siRNA. We found a significant upregulation of Col1A1, fibronectin, and vimentin after TGF-β1 stimulation in A549 cells. In contrast, a downregulation of Col1A1, fibronectin, and vimentin mRNA levels was observed in TGF-β1-stimulated OPN knockdown A549 cells. Therefore, the downregulation of OPN effectively reduced pulmonary fibrotic and EMT changes both in vitro and in vivo. Altogether, our results indicate that OPN siRNA exerts a protective effect on BLM-induced PF in mice. Our results provide a basis for the development of novel targeted therapeutic strategies for IPF.

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  • Low plasma apolipoprotein E-rich high-density lipoprotein levels in patients with metabolic syndrome Reviewed International journal

    Ryoko Shinohata, Yuhei Shiga, Shin-ichiro Miura, Satoshi Hirohata, Misako Shibakura, Tomoe Ueno-Iio, Shogo Watanabe, Yujiro Arao, Shinichi Usui

    CLINICA CHIMICA ACTA   510   531 - 536   2020.11

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    Background: High-density lipoprotein (HDL) containing apolipoprotein E (apoE-rich HDL) represents a small portion of plasma HDL. We recently established a method for measuring plasma apoE-rich HDL. This study aimed to investigate the relationship between metabolic syndrome (MetS) and apoE-rich HDL levels.Methods: The apoE-rich HDL-cholesterol (HDL-C) levels and metabolic characteristics of 113 patients were analyzed.Results: The MetS group (n = 58) had significantly lower apoE-rich HDL-C and a lower apoE-rich HDL-C/HDL-C ratio (apoE-HDL (%)) compared to the non-MetS group. The prevalence of MetS was increased when apoE-HDL (%) decreased. In simple regression analyses, apoE-HDL (%) was significantly inversely correlated with visceral fat area (r(s) = - 0.370, P < 0.001) and plasma triglycerides (r(s) = - 0.447, P < 0.001) and positively correlated with low-density lipoprotein (LDL) mean particle size (r(s) = 0.599, P < 0.001) and HDL mean particle size (r(s) = 0.512, P < 0.001). Stepwise multiple regression analysis revealed that LDL mean particle size, a component of the atherogenic lipoprotein profile, was an independent predictor of apoE-HDL (%) (adjusted R-2 = 0.409).Conclusions: Plasma apoE-rich HDL levels might be a valuable indicator of MetS. These findings may help further understand HDL subfraction analysis in cardiometabolic diseases.

    DOI: 10.1016/j.cca.2020.08.020

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  • Efficacy of an Adjunctive Electrophysiological Test–Guided Left Atrial Posterior Wall Isolation in Persistent Atrial Fibrillation Without a Left Atrial Low-Voltage Area Reviewed International journal

    Hirosuke Yamaji, Shunichi Higashiya, Takashi Murakami, Kazuyoshi Hina, Hiroshi Kawamura, Masaaki Murakami, Shigeshi Kamikawa, Satoshi Hirohata, Shozo Kusachi

    Circulation: Arrhythmia and Electrophysiology   13 ( 8 )   e008191   2020.8

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Ovid Technologies (Wolters Kluwer Health)  

    <sec>
    <title>Background:</title>
    Electrical remodeling precedes structural remodeling. In adjunctive left atrial (LA) low-voltage area (LVA) ablation to pulmonary vein isolation of atrial fibrillation (AF), LA areas without LVA have not been targeted for ablation. We studied the effect of adjunctive LA posterior wall isolation (PWI) on persistent AF without LA-LVA according to electrophysiological testing (EP test).


    </sec>
    <sec>
    <title>Methods:</title>
    We examined consecutive patients with persistent AF with (n=33) and without (n=111) LA-LVA. Patients without LA-LVA were randomly assigned to EP test–guided (n=57) and control (n=54) groups. In the EP test–guided group, an adjunctive PWI was performed in those with positive results (PWI subgroup; n=24), but not in those with negative results (n=33). The criteria for positive EP tests were an effective refractory period ≤180 ms, effective refractory period&gt;20 ms shorter than the other sites, and/or induction of AF/atrial tachycardia (AT) during measurements. LVA ablation was performed in the patients with LA-LVA.


    </sec>
    <sec>
    <title>Results:</title>

    During the follow-up period (62±33 weeks), the EP test–guided group had significantly lower recurrence rates (19%,11/57 versus 41%, 22/54,
    <italic>P</italic>
    =0.012) and higher Kaplan-Meier AF/AT–free survival curve rates than the control group (
    <italic>P</italic>
    =0.01). No significant differences in the recurrence and AF/AT–free survival curve rates between the PWI (positive EP test) and non-PWI (negative EP test) subgroups were observed. Therefore, PWI for positive EP tests reduced the AF/AT recurrence in the EP test–guided group. A stepwise Cox proportional hazard analyses identified EP test–guided ablation as a factor reducing the recurrence rate. The recurrence rates in the LA-LVA ablation group and EP test–guided group were similar.



    </sec>
    <sec>
    <title>Conclusions:</title>
    This pilot study proposed that an EP test–guided adjunctive PWI of persistent AF without LA-LVA potentially reduced AF/AT recurrences. The results suggest that there is an AF substrate in the LA with altered electrophysiological function even when there is no LA-LVA.


    </sec>
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    <title>Graphic Abstract:</title>

    A
    <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="graphic abstract">graphic abstract</ext-link>
    is available for this article.



    </sec>

    DOI: 10.1161/circep.119.008191

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  • Induction of CEMIP in Chondrocytes by Inflammatory Cytokines: Underlying Mechanisms and Potential Involvement in Osteoarthritis. Reviewed International journal

    Takashi Ohtsuki, Omer F Hatipoglu, Keiichi Asano, Junko Inagaki, Keiichiro Nishida, Satoshi Hirohata

    International journal of molecular sciences   21 ( 9 )   2020.4

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    In patients with osteoarthritis (OA), there is a decrease in both the concentration and molecular size of hyaluronan (HA) in the synovial fluid and cartilage. Cell migration-inducing hyaluronidase 1 (CEMIP), also known as hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID), was recently reported as an HA depolymerization-related molecule expressed in the cartilage of patients with OA. However, the underlying mechanism of CEMIP regulation is not well understood. We found that CEMIP expression was transiently increased by interleukine-1β (IL-1β) stimulation in chondrocytic cells. We also observed that ERK activation and NF-κB nuclear translocation were involved in the induction of CEMIP by IL-1β. In addition, both administration of HA and mechanical strain attenuated the CEMIP induction in IL-1β-stimulated chondrocytes. In conclusion, we clarified the regulatory mechanism of CEMIP in chondrocytes by inflammatory cytokines and suggested the potential involvement in osteoarthritis development.

    DOI: 10.3390/ijms21093140

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  • Deficiency of CD44 prevents thoracic aortic dissection in a murine model. Reviewed International journal

    Omer F Hatipoglu, Toru Miyoshi, Tomoko Yonezawa, Megumi Kondo, Naofumi Amioka, Masashi Yoshida, Satoshi Akagi, Kazufumi Nakamura, Satoshi Hirohata, Hiroshi Ito

    Scientific reports   10 ( 1 )   6869 - 6869   2020.4

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    Thoracic aortic dissection (TAD) is a life-threatening vascular disease. We showed that CD44, a widely distributed cell surface adhesion molecule, has an important role in inflammation. In this study, we examined the role of CD44 in the development of TAD. TAD was induced by the continuous infusion of β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, and angiotensin II (AngII) for 7 days in wild type (WT) mice and CD44 deficient (CD44-/-) mice. The incidence of TAD in CD44-/- mice was significantly reduced compared with WT mice (44% and 6%, p < 0.01). Next, to evaluate the initial changes, aortic tissues at 24 hours after BAPN/AngII infusion were examined. Neutrophil accumulation into thoracic aortic adventitia in CD44-/- mice was significantly decreased compared with that in WT mice (5.7 ± 0.3% and 1.6 ± 0.4%, p < 0.01). In addition, BAPN/AngII induced interleukin-6, interleukin-1β, matrix metalloproteinase-2 and matrix metalloproteinase-9 in WT mice, all of which were significantly reduced in CD44-/- mice (all p < 0.01). In vitro transmigration of neutrophils from CD44-/- mice through an endothelial monolayer was significantly decreased by 18% compared with WT mice (p < 0.01). Our findings indicate that CD44 has a critical role in TAD development in association with neutrophil infiltration into adventitia.

    DOI: 10.1038/s41598-020-63824-9

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  • Mechanical strain attenuates cytokine-induced ADAMTS9 expression via transient receptor potential vanilloid type 1. Reviewed International journal

    Takashi Ohtsuki, Akira Shinaoka, Kanae Kumagishi-Shinaoka, Keiichi Asano, Omer Faruk Hatipoglu, Junko Inagaki, Ken Takahashi, Toshitaka Oohashi, Keiichiro Nishida, Keiji Naruse, Satoshi Hirohata

    Experimental cell research   383 ( 2 )   111556 - 111556   2019.10

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:ELSEVIER INC  

    The synovial fluids of patients with osteoarthritis (OA) contain elevated levels of inflammatory cytokines, which induce the expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and of the matrix metalloproteinase (MMP) in chondrocytes. Mechanical strain has varying effects on organisms depending on the strength, cycle, and duration of the stressor; however, it is unclear under inflammatory stimulation how mechanical strain act on. Here, we show that mechanical strain attenuates inflammatory cytokine-induced expression of matrix-degrading enzymes. Cyclic tensile strain (CTS), as a mechanical stressor, attenuated interleukin (IL)-1β and tumor necrosis factor (TNF)-α-induced mRNA expression of ADAMTS4, ADAMTS9, and MMP-13 in normal chondrocytes (NHAC-kn) and in a chondrocytic cell line (OUMS-27). This effect was abolished by treating cells with mechano-gated channel inhibitors, such as gadolinium, transient receptor potential (TRP) family inhibitor, ruthenium red, and with pharmacological and small interfering RNA-mediated TRPV1 inhibition. Furthermore, nuclear factor κB (NF-κB) translocation from the cytoplasm to the nucleus resulting from cytokine stimulation was also abolished by CTS. These findings suggest that mechanosensors such as the TRPV protein are potential therapeutic targets in treating OA.

    DOI: 10.1016/j.yexcr.2019.111556

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  • Serum malondialdehyde-modified low-density lipoprotein levels on admission predict prognosis in patients with acute coronary syndrome undergoing percutaneous coronary intervention Reviewed International journal

    Naofumi Amioka, Toru Miyoshi, Hiroaki Otsuka, Daisuke Yamada, Atsushi Takaishi, Masayuki Ueeda, Satoshi Hirohata, Hiroshi Ito

    JOURNAL OF CARDIOLOGY   74 ( 3-4 )   258 - 266   2019.9

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    Background: Malondialdehyde-modified low-density lipoprotein (MDA-LDL) is a predictive marker of cardiovascular events in patients with stable angina pectoris. However, little is known about this marker in patients with acute coronary syndrome (ACS). We investigated the prognostic relevance of MDA-LDL to cardiovascular outcomes in patients with ACS.Methods: A total of 370 consecutive patients with ACS who underwent primary percutaneous coronary intervention (PCI) were enrolled from October 2009 to September 2014 at Mitoyo General Hospital. Serum MDA-LDL levels were measured at admission. The patients were divided into three tertile groups according to serum MDA-LDL levels. The primary outcomes were cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularization, and heart failure requiring hospital admission.Results: MDA-LDL levels in patients with acute myocardial infarction were significantly greater than those in patients with unstable angina pectoris (mean +/- standard deviation: 133 +/- 48 U/L vs.157 +/- 69 U/L, p = 0.001). During follow-up [472 (195-920) days], 82 (22%) events occurred. Kaplan-Meier analysis showed that patients in the highest MDA-LDL tertile had the worst prognosis (log-rank, p < 0.001). Cox regression analysis showed that serum MDA-LDL levels were an independent predictor of cardiovascular events after PCI in patients with ACS, even after adjustment for age, sex, body mass index, conventional cardiovascular risk factors, other lipid biomarkers, statin use on admission, cardiac biomarkers, and presence or absence of multivessel disease (hazard ratio: 1.80 per 1 standard deviation U/L increase, 95% confidence interval: 1.07-3.16, p = 0.027).Conclusion: Serum MDA-LDL levels on admission are a significant prognostic marker in patients with ACS who undergo successful PCI. (C) 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jjcc.2019.02.012

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  • High molecular weight hyaluronan protects cartilage from degradation by inhibiting aggrecanase expression. Reviewed International journal

    Takashi Ohtsuki, Keiichi Asano, Junko Inagaki, Akira Shinaoka, Kanae Kumagishi-Shinaoka, Mehmet Z Cilek, Omer F Hatipoglu, Toshitaka Oohashi, Keiichiro Nishida, Issei Komatsubara, Satoshi Hirohata

    Journal of orthopaedic research : official publication of the Orthopaedic Research Society   36 ( 12 )   3247 - 3255   2018.12

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY  

    Hyaluronan (HA) is an extracellular matrix (ECM) component of articular cartilage and has been used to treat patients with osteoarthritis (OA). A disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs) play an important role in cartilage degradation in OA. We have previously reported that ADAMTS4 and ADAMTS9 were induced by cytokine stimulation. However, the effect of HA on the cytokine-inducible ADAMTS9 has never been investigated. Moreover, it is unclear whether HA protects cartilage by suppressing aggrecan degradation. Here, we examined the effects of HA on ADAMTS expression in vitro and on cartilage degradation in vivo. ADAMTS9 expression was higher than that of the other aggrecanases (ADAMTS4 and 5) in human chondrocytes, chondrocytic cells, and rat cartilage. ADAMTS4 and 9 mRNA levels were upregulated in cytokine-stimulated chondrocytes and chondrocytic cells. Pre-incubation with HA significantly inhibited ADAMTS9 mRNA expression in cytokine-stimulated cells. In a rat OA model, Adamts5 and 9 mRNA levels were transiently increased after surgery; intra-articular HA injections attenuated the induction of Adamts5 and 9 mRNA. HA also blocked aggrecan cleavage by aggrecanase in OA rats in a molecular size-dependent manner. These results demonstrate that HA attenuates induced aggrecanases expression in OA and thereby protects articular cartilage degradation by this enzyme. Our findings provide insight into the molecular basis for the beneficial effects of HA in OA. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 36:3247-3255, 2018.

    DOI: 10.1002/jor.24126

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  • Non-alcoholic steatohepatitis aggravates nitric oxide synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rat model Reviewed International journal

    Shogo Watanabe, Shota Kumazaki, Shusei Yamamoto, Ikumi Sato, Kazuya Kitamori, Mari Mori, Yukio Yamori, Satoshi Hirohata

    INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY   99 ( 6 )   282 - 294   2018.12

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    Non-alcoholic steatohepatitis (NASH) is linked to increased cardiovascular risk, independent of the broad spectrum of metabolic syndrome risk factors. Stroke-prone (SP) spontaneously hypertensive rats (SHRSP5/Dmcr) fed a high-fat and high-cholesterol (HFC) diet developed hepatic lesions similar to those in human NASH pathology. These rats simultaneously developed lipid deposits in the mesenteric arteries, cardiac fibrosis, endothelial dysfunction and left ventricle (LV) diastolic dysfunction. However, the intermediary factors between NASH and cardiovascular disease are still unknown. We investigated whether NASH aggravates nitric oxide (NO) synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rats. Wistar Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 and fed the stroke-prone (SP) or HFC diets for 8 weeks. To induce NO synthase inhibition, N-omega-nitro-L-arginine methyl ester hydrochloride (L-NAME) mixed with drinking water was administered in the final 2 weeks. The NASH+ L-NAME group demonstrated the following characteristics related to arteriosclerosis and myocardial ischaemia: (a) LV systolic dysfunction with asynergy, (b) replacement fibrosis caused by the shedding of cardiomyocytes and (c) arterial lipid deposition and coronary occlusion secondary to endothelial dysfunction. These characteristics were not observed in the NASH or non-NASH+ L-NAME groups. The SHRSP5/Dmcr rat model demonstrates that NASH significantly aggravates cardiovascular risk.

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  • Differences in activated clotting time and initial heparin dosage during atrial fibrillation ablation for patients with edoxaban compared with warfarin Reviewed International journal

    Hirosuke Yamaji, Takashi Murakami, Kazuyoshi Hina, Shunichi Higashiya, Hiroshi Kawamura, Masaaki Murakami, Shigeshi Kamikawa, Satoshi Hirohata, Shozo Kusachi

    Journal of Cardiovascular Electrophysiology   29 ( 6 )   835 - 843   2018.6

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    Background: Different target activated clotting times (ACTs) during atrial fibrillation (AF) ablation have been proposed. Moreover, relationships between initial bolus dose of heparin at the start of AF ablation in patients receiving edoxaban anticoagulation therapy and ACT are unclear. Methods: Patients who received anticoagulation with uninterrupted warfarin (control
    n = 120) or interrupted edoxaban (n = 120) on the morning of day of ablation were studied. An initial dose of 100 U/kg heparin was administered as a reliable control for warfarin. Initial heparin doses of 120, 130, 140, or 150 U/kg were randomly administered to the edoxaban group. Results: Edoxaban group showed shorter baseline ACT before the procedure (130 ± 16 seconds) than the warfarin group (152 ± 26 seconds, P &lt
     0.0001). In the warfarin group, 100 U/kg heparin showed 361 ± 48 seconds 15-minute ACT. In the edoxaban group, an increase in initial dose induced prolongation of 15-minute ACT (i.e., 15-minute ACTs of 293 ± 56, 306 ± 39, 311 ± 45, and 319 ± 45 seconds for 120, 130, 140, and 150 U/kg initial doses, respectively). The total heparin required during the procedure was higher in the edoxaban group than in the warfarin group (109 ± 37 vs. 77 ± 21 U/kg/h, P &lt
     0.0001). The 120–150 U/kg dose of heparin in edoxaban group did not cause thromboembolic or major bleeding complications. Conclusion: Edoxaban interrupted on the day of ablation showed a shorter baseline ACT than uninterrupted warfarin. Edoxaban required a higher initial heparin dose to achieve a similar 15-minute ACT to warfarin. These results are useful for determining the initial heparin dose required to achieve variable target ACTs.

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  • Host-produced ADAMTS4 Inhibits Early-Stage Tumor Growth. Reviewed

    Keiichi Asano, Midori Edamatsu, Omer F Hatipoglu, Junko Inagaki, Mitsuaki Ono, Takashi Ohtsuki, Toshitaka Oohashi, Satoshi Hirohata

    Acta medica Okayama   72 ( 3 )   257 - 266   2018.6

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    Several research groups demonstrated that 'a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs (ADAMTS)'-family proteases play roles in cancer progression. However, the origins and contributions of these proteases are not known. Here, we demonstrate an association between host-produced ADAMTS4 and early-stage tumor growth. Murine Lewis lung carcinoma (LLC) tumors showed marked expressions of Adamts4 and Adamts5. We examined the contributions and distributions of host-derived Adamts4 and Adamts5 on tumor growth, using Adamts4LacZ/LacZ and Adamts5LacZ/LacZ knockout mice. Interestingly, the Adamts4LacZ/LacZ mice showed enhanced tumor growth compared to wild-type mice at 5-, 10- and 12-days post-inoculation, whereas the Adamts5LacZ/LacZ mice did not show significant differences in tumor growth. We next examined LacZ distribution in LLC tumor-bearing Adamts4LacZ/LacZ mice by β-galactosidase (β-gal) staining. We found that the β-gal-positive signals were strictly localized at the interior areas of the tumor at 10 days post-inoculation. Multiple staining demonstrated that most of the β-gal-positive cells were localized at the tumor vasculature in Adamts4LacZ/LacZ mice. Interestingly, β-gal-positive signals were not co-localized with biglycan after 10 days post-inoculation, excluding the biglycan cleavage by host-derived ADAMTS4. Taken together, these findings illustrate that host-derived ADAMTS4 was expressed at the tumor vessels and was associated with early-stage tumor growth.

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  • A high-fat and high-cholesterol diet induces cardiac fibrosis, vascular endothelial, and left ventricular diastolic dysfunction in shrsp5/dmcr rats Reviewed

    Shogo Watanabe, Shota Kumazaki, Katsuhiro Kusunoki, Terumi Inoue, Yui Maeda, Shinichi Usui, Ryoko Shinohata, Takashi Ohtsuki, Satoshi Hirohata, Shozo Kusachi, Kazuya Kitamori, Mari Mori, Yukio Yamori, Hisao Oka

    Journal of Atherosclerosis and Thrombosis   25 ( 5 )   439 - 453   2018

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    Aim: Non-alcoholic steatohepatitis (NASH) increases cardiovascular risk regardless of risk factors in metabolic syndrome. However, the intermediary factors between NASH and vascular disease are still unknown because a suitable animal model has never been established. The stroke-prone (SP) spontaneously hypertensive rat, SHRSP5/Dmcr, simultaneously develops hypertension, acute arterial lipid deposits in mesenteric arteries, and NASH when feed with a high-fat and high-cholesterol (HFC) diet. We investigated whether SHRSP5/Dmcr affected with NASH aggravates the cardiac or vascular dysfunction. Method: Wister Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 rats each, and fed with a SP or HFC diet. After 8 weeks of HFC or SP diet feeding, glucose and insulin resistance, echocardiography, blood biochemistry, histopathological staining, and endothelial function in aorta were evaluated. Results: We demonstrate that SHRSP5/Dmcr rats fed with a HFC diet presented with cardiac and vascular dysfunction caused by cardiac fibrosis, endothelial dysfunction, and left ventricular diastolic dysfunction, in association with NASH and hypertension. These cardiac and vascular dysfunctions were aggravated and not associated with the presence of hypertension, glucose metabolism disorder, and/or obesity. Conclusions: SHRSP5/Dmcr rats may be a suitable animal model for elucidating the organ interaction between NASH and cardiac or vascular dysfunction.

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  • Stromal Versican Regulates Tumor Growth by Promoting Angiogenesis Reviewed International journal

    Keiichi Asano, Courtney M. Nelson, Sumeda Nandadasa, Noriko Aramaki-Hattori, Daniel J. Lindner, Tyler Alban, Junko Inagaki, Takashi Ohtsuki, Toshitaka Oohashi, Suneel S. Apte, Satoshi Hirohata

    SCIENTIFIC REPORTS   7 ( 1 )   2101 - 2105   2017.12

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    The proteoglycan versican is implicated in growth and metastases of several cancers. Here we investigated a potential contribution of stromal versican to tumor growth and angiogenesis. We initially determined versican expression by several cancer cell lines. Among these, MDA-MB231 and B16F10 had none to minimal expression in contrast to Lewis lung carcinoma (LLC). Notably, tumors arising from these cell lines had higher versican levels than the cell lines themselves suggesting a contribution from the host-derived tumor stroma. In LLC-derived tumors, both the tumor and stroma expressed versican at high levels. Thus, tumor stroma can make a significant contribution to tumor versican content. Versican localized preferentially to the vicinity of tumor vasculature and macrophages in the tumor. However, an ADAMTS protease-generated versican fragment uniquely localized to vascular endothelium. To specifically determine the impact of host/stroma-derived versican we therefore compared growth of tumors from B16F10 cells, which produced littleversican, in Vcan(hdf/+) mice and wild-type littermates. Tumors in Vcan(hdf/+) mice had reduced growth with a lower capillary density and accumulation of capillaries at the tumor periphery. These findings illustrate the variability of tumor cell line expression of versican, and demonstrate that versican is consistently contributed by the stromal tissue, where it contributes to tumor angiogenesis.

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  • MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1 Reviewed International journal

    Kazuhiro Yamamoto, Hiroshi Okano, Wakako Miyagawa, Robert Visse, Yasuyuki Shitomi, Salvatore Santamaria, Jayesh Dudhia, Linda Troeberg, Dudley K. Strickland, Satoshi Hirohata, Hideaki Nagase

    MATRIX BIOLOGY   56   57 - 73   2016.12

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    Matrix metalloproteinase 13 (MMP-13) degrades collagenous extracellular matrix and its aberrant activity associates with diseases such as arthritis, cancer, atherosclerosis and fibrosis. The wide range of MMP-13 proteolytic capacity suggests that it is a powerful, potentially destructive proteinase and thus it has been believed that MMP-13 is not produced in most adult human tissues in the steady state. Present study has revealed that human chondrocytes isolated from healthy adults constitutively express and secrete MMP-13, but that it is rapidly endocytosed and degraded by chondrocytes. Both pro- and activated MMP-13 bind to clusters II and III of low-density lipoprotein (LDL) receptor-related protein 1 (LRP1). Domain deletion studies indicated that the hemopexin domain is responsible for this interaction. Binding competition between MMP-13 and ADAMTS-4,-5 or TIMP-3, which also bind to cluster II, further shown that the MMP-13 binding site within cluster II is different from those of ADAMTS-4,-5 or TIMP-3. MMP-13 is therefore co-endocytosed with ADAMTS-5 and TIMP-3 by human chondrocytes. These findings indicate that MMP-13 may play a role on physiological turnover of cartilage extracellular matrix and that LRP1 is a key modulator of extracellular levels of MMP-13 and its internalization is independent of the levels of ADAMTS-4,-5 and TIMP-3. (C) 2016 The Authors. Published by Elsevier B.V.

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  • Loss of ADAMTS4 reduces high fat diet-induced atherosclerosis and enhances plaque stability in ApoE(-/-) mice Reviewed International journal

    Saran Kumar, Mo Chen, Yan Li, Fiona H. S. Wong, Chung Wee Thiam, Md Zakir Hossain, Kian Keong Poh, Satoshi Hirohata, Hiroko Ogawa, Veronique Angeli, Ruowen Ge

    SCIENTIFIC REPORTS   6   31130 - 31130   2016.8

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    Atherosclerosis is a chronic inflammatory disease characterized by formation of lipid-rich plaques on the inner walls of arteries. ADAMTS4 (a disintegrin-like and metalloproteinase with thrombospondin motifs-4) is a secreted proteinase that regulates versican turnover in the arterial wall and atherosclerotic plaques. Recent reports indicated elevated ADAMTS4 level in human atherosclerotic plaques and in the plasma of acute coronary syndrome patients. Nevertheless, whether increased ADAMTS4 is a consequence of atherosclerosis or ADAMTS4 has a causal role in atherogenesis remains unknown. In this work, we investigated the role of ADAMTS4 in diet induced atherosclerosis using apolipoprotein E deficient (ApoE(-/-)) and Adamts4 knockout mice. We show that ADAMTS4 expression increases in plaques as atherosclerosis progresses in ApoE(-/-) mice. ApoE(-/-) Adamts4(-/-) double knockout mice presented a significant reduction in plaque burden at 18 weeks of age. Loss of ADAMTS4 lead to a more stable plaque phenotype with a significantly reduced plaque vulnerability index characterized by reduced lipid content and macrophages accompanied with a significant increase in smooth muscle cells, collagen deposition and fibrotic cap thickness. The reduced atherosclerosis is accompanied by an altered plasma inflammatory cytokine profile. These results demonstrate for the first time that ADAMTS4 contributes to diet induced atherosclerosis in ApoE(-/-) mice.

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  • Interleukin-1 induced nuclear factor-B binds to a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 9 promoter in human chondrosarcoma cells Reviewed International journal

    Aynur Altuntas, Sevil Oskay Halacli, Ozlem Cakmak, Gonul Erden, Sumeyya Akyol, Veli Ugurcu, Satoshi Hirohata, Kadir Demircan

    MOLECULAR MEDICINE REPORTS   12 ( 1 )   595 - 600   2015.7

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    Nuclear factor-B (NF-B) is involved in the regulation of inflammation-associated genes. NF-B forms dimers which bind with sequences referred to as NF-B sites (9-11 bp). A disintegrin-like and metalloproteinase with thrombospondin type 1 motif 9 (ADAMTS9) is a type of proteoglycanase, which proteolytically cleaves versican and aggrecan. ADAMTS9 is a cytokine-inducible gene that contains binding sites for NF-B within its promoter region. Interleukin-1 (IL-1) affects cartilage metabolism and is involved in the NF-B pathway. It is therefore hypothesized that NF-B binding with ADAMTS9 promoters may activate IL-1, thereby promoting chondrocytic cell growth. In the present study, the OUMS-27 chondrocytic human chondrosarcoma cell line was treated with IL-1 with or without inhibitors of NF-B signaling pathways. Chromatin immunoprecipitation (ChIP) and electromobility shift assays (EMSA) were conducted order to analyze the binding of NF-B with the ADAMTS9 promoter region. NF-B-p65 subunit phosphorylation was promoted in IL-1-treated cells, which were not treated with inhibitors of NF-B signaling pathways. By contrast, NF-B-p65 subunit phosphorylation was inhibited in cells that had been treated with BAY-117085, an NF-B pathway inhibitor. ChIP and EMSA assays demonstrated that, following treatment with IL-1, NF-B-p65 bound to elements located at -1177 and -1335 in the ADAMTS9 promoter region, in contrast to the untreated samples. The results of the present study suggested that NF-B may be involved in IL-1-induced activation of ADAMTS9 in human chondrocytes.

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  • ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor. Reviewed International journal

    Junko Inagaki, Katsuyuki Takahashi, Hiroko Ogawa, Keiichi Asano, Omer Faruk Hatipoglu, Mehmet Zeynel Cilek, Masanari Obika, Takashi Ohtsuki, Matthias Hofmann, Shozo Kusachi, Yoshifumi Ninomiya, Satoshi Hirohata

    Experimental cell research   323 ( 2 )   263 - 75   2014.5

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    Angiogenesis and lymphangiogenesis play roles in malignant tumor progression, dissemination, and metastasis. ADAMTS1, a member of the matrix metalloproteinase family, is known to inhibit angiogenesis. Recombinant ADAMTS1 was shown to strongly inhibit angiogenesis. We investigated whether ADAMTS1 inhibited lymphangiogenesis in the present study. We examined cell proliferation and cell migration in normal human dermal lymphatic microvascular endothelial cells (HMVEC-dLy) transduced with or without adenoviral human ADAMTS1 gene therapy. We then examined the VEGFC/VEGFR3 signal transduction pathway in ADAMTS1-transduced HMVEC-dLy. Cell proliferation and tube formation in Matrigel were significantly lower with transduced ADAMTS1 than with control (non-transduced HMVEC-dLy). The phosphorylation of VEGFR3 was also attenuated by ADAMTS1 gene therapy in HMVEC-dLy. Immunoprecipitation assays revealed that ADAMTS1 formed a complex with VEGFC. Our results demonstrated that ADAMTS1 inhibited lymphangiogenesis in vitro. The data highlight the new function of ADAMTS1 in the regulation of lymphangiogenesis and the therapeutic potential of ADAMTS1 in cancer therapy.

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  • ADAMTS4 and ADAMTS5 Knockout Mice Are Protected from Versican but Not Aggrecan or Brevican Proteolysis during Spinal Cord Injury International journal

    Kadir Demircan, Vehap Topcu, Tomoyuki Takigawa, Sumeyya Akyol, Tomoko Yonezawa, Gulfer Ozturk, Veli Ugurcu, Rukiye Hasgul, M. Ramazan Yigitoglu, Omer Akyol, Daniel R. McCulloch, Satoshi Hirohata

    BIOMED RESEARCH INTERNATIONAL   2014 ( 2014 )   693746 - 693746   2014

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    The chondroitin sulfate proteoglycans (CSPGs) aggrecan, versican, and brevican are large aggregating extracellular matrix molecules that inhibit axonal growth of the mature central nervous system (CNS). ADAMTS proteoglycanases, including ADAMTS4 and ADAMTS5, degrade CSPGs, representing potential targets for ameliorating axonal growth-inhibition by CSPG accumulation after CNS injury. We investigated the proteolysis of CSPGs in mice homozygous for Adamts4 or Adamts5 null alleles after spinal cord injury (SCI). ADAMTS-derived 50-60 kDa aggrecan and 50 kDa brevican fragments were observed in Adamts4-/-, Adamts5-/-, and wt mice but not in the sham-operated group. By contrast Adamts4-/- and Adamts5-/- mice were both protected from versican proteolysis with an ADAMTS-generated 70 kDa versican fragment predominately observed in WT mice. ADAMTS1, ADAMTS9, and ADAMTS15 were detected by Western blot in Adamts4-/- mice' spinal cords after SCI. Immunohistochemistry showed astrocyte accumulation at the injury site. These data indicate that aggrecan and brevican proteolysis is compensated in Adamts4-/- or Adamts5-/- mice by ADAMTS proteoglycanase family members but a threshold of versican proteolysis is sensitive to the loss of a single ADAMTS proteoglycanase during SCI. We show robust ADAMTS activity after SCI and exemplify the requirement for collective proteolysis for effective CSPG clearance during SCI.

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  • Augmentation of ADAMTS9 gene expression by IL-1 beta is reversed by NF kappa B and MAPK inhibitors, but not PI3 kinase inhibitors Reviewed International journal

    Sema Uysal, Zahide Nur Unal, Serpil Erdogan, Sumeyya Akyol, M. Ramazan Yigitoglu, Satoshi Hirohata, Bunyamin Isik, Kadir Demircan

    CELL BIOCHEMISTRY AND FUNCTION   31 ( 7 )   539 - 544   2013.10

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    The pathways involved in the regulation of a disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9) expression have not yet been elucidated. Therefore, the aim of this study was to investigate the involvement of nuclear factor-B (NF-B), mitogen activated protein kinases (MAPK) and Phosphatidylinositol 3-kinase (PI3 kinase) in ADAMTS9 gene regulation, with special focus on the involvement of NF-B in IL-1-induced ADAMTS9 expression. The OUMS-27 chondrosarcoma cells were exposed to IL-1. They were pretreated with 20M PD98059 (specific inhibitor of p44/42 kinase), 10M SB203580 (specific inhibitor of p38 kinase), 20M SB600125 (MAPK inhibitor), and 1M Wortmannin and 10M LY294002 (specific inhibitors of PI3 kinase) for 30min and subsequently incubated with IL-1. For the effects of NF-B and IB inhibitors, cells were pretreated with curcumin or BAY117085 for 30min and subsequently incubated with IL-1. BAY117085 and different concentrations of curcumin were applied to the cells just after the first experiment to determine their concentration effect on ADAMTS9 gene expression. After total RNA was extracted, they were reversely transcribed with random primers and then real-time polymerase chain reaction (PCR) was performed on cDNA samples. There was a significant difference between control and stimulated cells in terms of ADAMTS9/-actin ratio. Wortmannin and LY294002 did not have any repressive effect on the OUMS-27 whereas SB203580 and SP600125 were found to decrease the expression of ADAMTS9 gene. BAY 117085 and curcumin, which are two NF-B inhibitors, led to a decrease in the ratio of ADAMTS9/-actin. As a conclusion, the pathways MAPK and NF-B were thought to be responsible pathways for the induction of ADAMTS9 gene. Copyright (c) 2012 John Wiley & Sons, Ltd.

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  • Vascular endothelial growth factor C-induced lymphangiogenesis decreases tumor interstitial fluid pressure and tumor. Reviewed International journal

    Matthias Hofmann, Ralph Pflanzer, Nadja Nicole Zoller, August Bernd, Roland Kaufmann, Diamant Thaci, Jurgen Bereiter-Hahn, Satoshi Hirohata, Stefan Kippenberger

    Translational oncology   6 ( 4 )   398 - 404   2013.8

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    Characteristically, most solid tumors exhibit an increased tumor interstitial fluid pressure (TIFP) that directly contributes to the lowered uptake of macromolecular therapeutics into the tumor interstitium. Abnormalities in the tumor-associated lymph vessels are a central brick in the development and prolonged sustaining of an increased TIFP. In the current study, vascular endothelial growth factor C (VEGF-C) was used to enhance tumor-associated lymphangiogenesis as a new mechanism to actively reduce the TIFP by increased lymphatic drainage of the tumor tissue. Human A431 epidermoid vulva carcinoma cells were inoculated in NMRI nu/nu mice to generate a xenograft mouse model. Seven days after tumor cell injection, VEGF-C was peritumorally injected to induce lymphangiogenesis. Tumor growth and TIFP was lowered significantly over time in VEGF-C-treated tumors in comparison to control or VEGF-A-treated animals. These data demonstrate for the first time that actively induced lymphangiogenesis can lower the TIFP in a xenograft tumor model and apparently reduce tumor growth. This model represents a novel approach to modulate biomechanical properties of the tumor interstitium enabling a lowering of TIFP in vivo.

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  • ADAMTS1, ADAMTS5, ADAMTS9 and aggrecanase-generated proteoglycan fragments are induced following spinal cord injury in mouse Reviewed International journal

    Kadir Demircan, Tomoko Yonezawa, Tomoyuki Takigawa, Vehap Topcu, Serpil Erdogan, Fatma Ucar, Ferah Armutcu, M. Ramazan Yigitoglu, Yoshifumi Ninomiya, Satoshi Hirohata

    NEUROSCIENCE LETTERS   544   25 - 30   2013.6

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    ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) proteinases are involved in a variety of biological processes such as angiogenesis, cancer and arthritis. ADAMTSs appears to be responsible for the cleavage of proteoglycans in several tissues including brain and cartilage. Chondroitin sulfate proteoglycans (CSPGs) maintains the integrity of the brain extracellular matrix and major inhibitory contributors for glial scar and neural plasticity. The activity of aggrecanases in the central nervous system (CNS)has been reported. ADAMTSs are an enzyme degrading CSPGs in the brain. However, there is a little knowledge regarding ADAMTSs in the CNS. We investigated the expression levels of ADAMTSs mRNAs by RT-PCR after spinal cord injury in mouse. Transcripts encoding 4 of the 19 known ADAMTSs were evaluated in the mouse spinal cord following injury. ADAMTS1, -5 and -9 expression levels were found to be upregulated. No change was observed in ADAMTS4 expression. By means of immunohistochemistry, ADAMTSs were detected in the astrocytes implying its cellular source in SCI. Western blot analyses indicated that aggrecanase-generated proteoglycan fragments are produced after SCI. (c) 2013 Elsevier Ireland Ltd. All rights reserved.

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  • Eosinophil cationic protein enhances stabilization of beta-catenin during cardiomyocyte differentiation in P19CL6 embryonal carcinoma cells Reviewed International journal

    Guoliang Jin, Akifumi Mizutani, Takayuki Fukuda, Takayuki Otani, Ting Yan, Marta Prieto Vila, Hiroshi Murakami, Takayuki Kudoh, Satoshi Hirohata, Tomonari Kasai, David S. Salomon, Masaharu Seno

    MOLECULAR BIOLOGY REPORTS   40 ( 4 )   3165 - 3171   2013.4

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    Prior to gastrulation, the Wnt signaling pathway through stabilized beta-catenin enhances the differentiation of mouse ES cell into cardiomyocytes. We have recently shown that cardiomyocyte differentiation is enhanced by eosinophil cationic protein (ECP) through accelerated expression of marker genes of early cardiac differentiation. Furthermore, ECP enhanced the expression of Wnt3a in P19CL6 cells which were stimulated to differentiate into cardiomyocytes by DMSO. Following these findings, we evaluated in this study the potential of ECP to activate the Wnt/beta-catenin signaling pathway during cardiomyocyte differentiation. Analysis by real time qPCR revealed that ECP increased the expression of Frizzled genes such as Frizzled-1, -2, -4 and -10 in P19CL6 cells in the presence of DMSO. The increased expression of those Wnt receptors was found to inhibit the phosphorylation of beta-catenin resulting in the stabilization and translocation of beta-catenin into the nucleus of P19CL6 cells during the early stages of cardiomyocyte differentiation. When assessed for beta-catenin/TCF transcriptional activity with a TCF-luciferase (TOP/FOP) assay, ECP enhanced luciferase activity in P19CL6 cells during 48 h after transfection with TOP/FOP flash reporter in a stoichiometric manner. Collectively, this suggests that ECP can activate a canonical Wnt/beta-catenin signaling pathway by enhancing the stabilization of beta-catenin during cardiomyocyte differentiation.

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  • Tumor growth inhibitory effect of ADAMTS1 is accompanied by the inhibition of tumor angiogenesis. Reviewed International journal

    Masanari Obika, Hiroko Ogawa, Katsuyuki Takahashi, Jiayi Li, Omer Faruk Hatipoglu, Mehmet Zeynel Cilek, Toru Miyoshi, Junko Inagaki, Takashi Ohtsuki, Shozo Kusachi, Yoshifumi Ninomiya, Satoshi Hirohata

    Cancer science   103 ( 10 )   1889 - 97   2012.10

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    Angiogenesis plays an important role in tumor progression. Several reports have demonstrated that a disintegrin and metalloproteinase with thrombospondin motifs1 (ADAMTS1) inhibited angiogenesis via multiple mechanisms. The aim of this study was to investigate the effect of ADAMTS1 on endothelial cells in vitro and on tumor growth with regard to angiogenesis in vivo. We examined the effects of the transfection of ADAMTS1 using two constructs, full-length ADAMTS1 (full ADAMTS1) and catalytic domain-deleted ADAMTS1 (delta ADAMTS1). Transfection of both the full ADAMTS1 and delta ADAMTS1 gene constructs demonstrated the secretion of tagged-ADAMTS1 protein into the conditioned medium, so we examined the effects of ADAMTS1-containing conditioned medium on endothelial cells. Both types of conditioned media inhibited endothelial tube formation, and this effect was completely abolished after immunoprecipitation of the secreted protein from the medium. Both types of conditioned media also inhibited endothelial cell migration and proliferation. We then examined the impact of ADAMTS1 on endothelial cell apoptosis. Both conditioned media increased the number of Annexin V-positive endothelial cells and caspase-3 activity and this effect was attenuated when z-vad was added. These results indicated that ADAMTS1 induced endothelial cell apoptosis. We next examined the effects of ADAMTS1 gene transfer into tumor-bearing mice. Both full ADAMTS1 and delta ADAMTS1 significantly inhibited the subcutaneous tumor growth. Collectively, our results demonstrated that ADAMTS1 gene transfer inhibited angiogenesis in vitro and in vivo, likely as a result of the induction of endothelial cell apoptosis by ADAMTS1 that occurs independent of the protease activity.

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  • Eosinophil cationic protein enhances cardiomyocyte differentiation of P19CL6 embryonal carcinoma cells by stimulating the FGF receptor signaling pathway Reviewed International journal

    Guoliang Jin, Akifumi Mizutani, Takayuki Fukuda, Ling Chen, Keisuke Nakanishi, Ting Yan, Takayuki Kudoh, Satoshi Hirohata, Tomonari Kasai, Hiroshi Murakami, David S. Salomon, Masaharu Seno

    GROWTH FACTORS   30 ( 5 )   344 - 355   2012.10

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    We investigated the functional role of eosinophil cationic protein (ECP) in regulating cardiomyogenesis using mouse P19CL6 embryonic carcinoma cells. ECP was confirmed to accelerate the cardiomyocyte differentiation of P19CL6 cells by enhancing the rate and area size of beating of cardiomyocyte and by facilitating the expression of cardiomyocyte-specific genes, such as GATA4 and alpha-MHC. Since cardiomyocyte differentiation in vivo is considered to follow mesoderm induction, the induction of Brachyury, a marker of mesoderm, was assessed. Brachyury expression was found to be enhanced after the addition of ECP. This enhancement was due to the stimulation of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation by ECP. In this context, treatment with SU5402, an inhibitor of fibroblast growth factor (FGF) receptor 1, suppressed Brachyury expression, phosphorylation of ERK1/2, and cardiomyocyte differentiation induced by ECP. We concluded that ECP might induce mesoderm differentiation through FGF signaling pathway and enhance subsequent cardiomyocyte differentiation in concert with dimethyl sulfoxide in P19CL6 cells. ECP may be a novel factor for cardiomyocyte differentiation, which should be very useful to prepare adequate numbers of cardiomyocytes for therapeutic cell transplantation.

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  • Four-year clinical outcomes of the OLIVUS-Ex (impact of Olmesartan on progression of coronary atherosclerosis: Evaluation by intravascular ultrasound) extension trial Reviewed International journal

    Atsushi Hirohata, Keizo Yamamoto, Toru Miyoshi, Kunihiko Hatanaka, Satoshi Hirohata, Hitoshi Yamawaki, Issei Komatsubara, Eiki Hirose, Yuhei Kobayashi, Keisuke Ohkawa, Minako Ohara, Hiroya Takafuji, Fumihiko Sano, Yuko Toyama, Shozo Kusachi, Tohru Ohe, Hiroshi Ito

    ATHEROSCLEROSIS   220 ( 1 )   134 - 138   2012.1

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    Background: The previous OLIVUS trial reported a positive role in achieving a lower rate of coronary atheroma progression through the administration of Olmesartan, an angiotension-II receptor blocking agent (ARB), for stable angina pectoris (SAP) patients requiring percutaneous coronary intervention (PCI). However, the benefits between ARB administration on long-term clinical outcomes and serial atheroma changes by IVUS remain unclear. Thus, we examined the 4-year clinical outcomes from OLIVUS according to treatment strategy with Olmesartan.
    Methods: Serial volumetric IVUS examinations (baseline and 14 months) were performed in 247 patients with hypertension and SAP. When these patients underwent PCI for culprit lesions, IVUS was performed in their non-culprit vessels. Patients were randomly assigned to receive 20-40mg of Olmesartan or control, and treated with a combination of beta-blockers, calcium channel blockers, glycemic control agents and/or statins per physician's guidance. Four-year clinical outcomes and annual progression rate of atherosclerosis, assessed by serial IVUS, were compared with major adverse cardio-and cerebrovascular events (MACCE).
    Results: Cumulative event-free survival was significantly higher in the Olmesartan group than in the control group (p = 0.04; log-rank test). By adjusting for validated prognosticators, Olmesartan administration was identified as a good predictor of MACCE (p = 0.041). On the other hand, patients with adverse events (n = 31) had larger annual atheroma progression than the rest of the population (23.8% vs. 2.1%, p &lt; 0.001).
    Conclusions: Olmesartan therapy appears to confer improved long-term clinical outcomes. Atheroma volume changes, assessed by IVUS, seem to be a reliable surrogate for future major adverse cardio-and cerebrovascular events in this study cohort. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

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  • Association of increased plasma adipocyte fatty acid-binding protein with coronary artery disease in non-elderly men Reviewed International journal

    Masayuki Doi, Toru Miyoshi, Satoshi Hirohata, Kazufumi Nakamura, Shinichi Usui, Ko Takeda, Mutsumi Iwamoto, Shozo Kusachi, Kengo Kusano, Hiroshi Ito

    CARDIOVASCULAR DIABETOLOGY   10   44 - 44   2011.5

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    Background: Adipocyte fatty acid-binding protein (A-FABP) has been reported to play critical roles in the development of atherosclerosis. We investigated whether an increased in plasma A-FABP level can be independently associated with the presence of coronary artery disease (CAD).
    Methods: Two hundred eleven consecutive male patients (mean age: 66 years, range: 33-87 years) were enrolled from inpatients who underwent coronary angiography. Age-matched male subjects (n = 211) having no evidence of CAD served as controls. Plasma A-FABP levels were measured by enzyme-linked immunosorbent assays.
    Results: Plasma A-FABP levels in CAD patients were significantly higher than in control subjects (median [IQR], 20.6 [15.7-27.8] ng/mL vs. 15.1 [11.7-19.9] ng/mL, p &lt; 0.01). Multivariate logistic regression analysis revealed that an increased plasma A-FABP level was independently associated with the presence of CAD in all subjects (adjusted odds ratio: 1.76, 95% confidence interval: 1.14 to 2.70, p = 0.01). Furthermore, sub-analysis based on age showed that this association remained significant in subjects aged &lt; 65 years (adjusted odds ratio: 3.06, 95% confidence interval: 1.34 to 6.98, p &lt; 0.01), but not in subjects aged &gt;= 65 years.
    Conclusions: Increased plasma A-FABP in non-elderly men had a significant association with the presence of CAD, independent of established CAD risk factors.

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  • Regulation of mechanical stress-induced MMP-13 and ADAMTS-5 expression by RUNX-2 transcriptional factor in SW1353 chondrocyte-like cells Reviewed

    T. Tetsunaga, K. Nishida, T. Furumatsu, K. Naruse, S. Hirohata, A. Yoshida, T. Saito, T. Ozaki

    OSTEOARTHRITIS AND CARTILAGE   19 ( 2 )   222 - 232   2011.2

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    Objective: To investigate the mechanism of mechanical stress-induced expression and regulation of aggrecanases and examine the role of runt-related transcription factor 2 (RUNX-2) in chondrocyte-like cells.
    Methods: SW1353 cells were seeded onto stretch chambers at a concentration of 5 x 10(4) cells/chamber, and a uni-axial cyclic tensile strain (CTS) (0.5 Hz, 10% stretch) was applied for 30 min. Total RNA was extracted, reverse transcribed, and analyzed by polymerase chain reaction (PCR) and real-time PCR. RUNX-2 overexpression and small interfering RNA (siRNA) targeting RUNX-2 were used to investigate the role of RUNX-2 in CTS-induced gene expression. The involvement of diverse mitogen-activated protein kinase (MAPK) pathways in the activation of RUNX-2, MMP-13 and ADAMTS-5 during CTS was examined by Western blotting.
    Results: CTS induced expression of RUNX-2, MMP-13, ADAMTS-4, -5, and -9. Overexpression of RUNX-2 up-regulated expression of MMP-13 and ADAMTS-5, whereas RUNX-2 siRNA resulted in significant down-regulation of mechanically-induced MMP-13 and ADAMTS-5 expression. CTS induced activation of p38 MAPK, and CTS induction of RUNX-2. MMP-13 and ADAMTS-5 mRNA was down-regulated by the selective p38 MAPK inhibitor SB203580 but not by the p44/42 MAPK inhibitor U0126, or the JNK MAPK inhibitor JNK inhibitor II.
    Conclusions: RUNX-2 might have a role as a key downstream mediator of p38&apos;s ability to regulate mechanical stress-induced MMP-13 and ADAMTS-5 expression. (C) 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

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  • AHR, a novel acute hypoxia-response sequence, drives reporter gene expression under hypoxia in vitro and in vivo. Reviewed International journal

    Mehmet Zeynel Cilek, Satoshi Hirohata, Omer Faruk Hatipoglu, Hiroko Ogawa, Toru Miyoshi, Junko Inagaki, Takashi Ohtsuki, Hiroshi Harada, Shigeshi Kamikawa, Shozo Kusachi, Yoshifumi Ninomiya

    Cell biology international   35 ( 1 )   1 - 8   2011.1

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    ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is an early immediate gene. We have previously reported that ADAMTS1 was strongly induced by hypoxia. In this study, we investigated whether ADAMTS1 promoter-driven reporter signal is detectable by acute hypoxia. We constructed the GFP (green fluorescent protein) expression vector [AHR (acute hypoxia-response sequence)-GFP] under the control of ADAMTS1 promoter and compared it with the constitutive GFP-expressing vector under the control of CMV (cytomegalovirus promoter-GFP). We transduced AHR-GFP and examined whether GFP signals can be detected under the acute hypoxia. When the human umbilical vein [HUVEC (human umbilical vein endothelial cells)] was transduced under normoxia, there were few GFP signals, while CMV-GFP showed considerable GFP signals. When HUVEC was stimulated with hypoxia, GFP signals from AHR-GFP gene were induced under hypoxic conditions. Notably, the GFP signals peaked at 3 h under hypoxia. In ischaemic hind limb model, transduced AHR-GFP showed hypoxic induction of GFP signals. In summary, we have demonstrated that the AHR system induced the reporter gene expression by acute hypoxia, and its induction is transient. This is the first report showing the unique acute hypoxia-activated gene expression system.

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  • Connective tissue growth factor induction in a pressure-overloaded heart ameliorated by the angiotensin II type 1 receptor blocker olmesartan Reviewed International journal

    Mutsumi Iwamoto, Satoshi Hirohata, Hiroko Ogawa, Takashi Ohtsuki, Ryoko Shinohata, Toru Miyoshi, O. Faruk Hatipoglu, Shozo Kusachi, Kazuhide Yamamoto, Yoshifumi Ninomiya

    HYPERTENSION RESEARCH   33 ( 12 )   1305 - 1311   2010.12

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    Connective tissue growth factor (CTGF) is a secreted protein that regulates fibrosis. We hypothesized that CTGF is induced in a pressure-overloaded (PO) heart and that blocking the angiotensin II type 1 receptor would reduce CTGF expression. Accordingly, we administered olmesartan and compared its effects with other antihypertensive drugs in a PO heart. CTGF induction was determined in a rat PO model, and olmesartan, hydralazine or saline was continuously administered. The effects of olmesartan on CTGF induction, myocyte hypertrophy and fibrosis were evaluated. The effect of olmesartan on cardiac function was also examined in CTGF-and transforming growth factor-beta 1 (TGF-beta 1)-infused rats. CTGF was increased in the PO heart 3 days after aortic banding and was markedly distributed around the perivascular fibrotic area. After 28 days, blood pressure was not significantly different in the olmesartan and hydralazine groups, but olmesartan treatment reduced CTGF distribution in PO hearts. Olmesartan was associated with a significantly reduced myocyte hypertrophy index (4.77 +/- 0.48 for olmesartan and 6.05 +/- 1.45 for saline, P&lt;0.01), fibrosis area (32.0 +/- 15.5% compared with the saline group, P&lt;0.05) and serum TGF-beta 1 level (62.6 +/- 10.6 ng ml(-1) for olmesartan and 84.4 +/- 7.2 ng ml(-1) for hydralazine, P&lt;0.05). In addition, cardiac function was significantly preserved in the olmesartan group compared with the saline group. Finally, olmesartan ameliorated the cardiac dysfunction in CTGF-and TGF-beta 1-infused rats. Olmesartan attenuated CTGF induction, reduced perivascular fibrosis and ameliorated cardiac dysfunction in a PO heart. Our results provide insight into the beneficial effects of olmesartan on PO hearts, independent of blood-pressure lowering. Hypertension Research (2010) 33, 1305-1311; doi:10.1038/hr.2010.189; published online 14 October 2010

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  • Increased activity and expression of histone deacetylase 1 in relation to tumor necrosis factor-alpha in synovial tissue of rheumatoid arthritis Reviewed International journal

    Tomoko Kawabata, Keiichiro Nishida, Koji Takasugi, Hiroko Ogawa, Kenei Sada, Yasutaka Kadota, Junko Inagaki, Satoshi Hirohata, Yoshifumi Ninomiya, Hirofumi Makino

    Arthritis Research and Therapy   12 ( 4 )   R133   2010.7

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    Introduction: The purpose of this study was to investigate the profile of histone deacetylase (HDAC) expression in the synovial tissue of rheumatoid arthritis (RA) compared with that of normal control and osteoarthritis (OA), and to examine whether there is a link between HDAC activity and synovial inflammation.Methods: HDAC activity and histone acetyltransferase (HAT) activity were determined in nuclear extracts of total synovial tissue surgically obtained from normal, OA and RA joints. The level of cytoplasmic tumor necrosis factor a (TNFα) fraction was measured by ELISA. Total RNA of synovial tissue was used for RT-PCR of HDAC1-8. In synovial fibroblasts from RA (RASFs), the effects of TNFα on nuclear HDAC activity and class I HDACs (1, 2, 3, 8) mRNA expressions were examined by quantitative real-time PCR. The protein expression and distribution of class I HDACs were examined by Western blotting.Results: Nuclear HDAC activity was significantly higher in RA than in OA and normal controls and correlated with the amount of cytoplasmic TNFα. The mRNA expression of HDAC1 in RA synovial tissue was higher than in OA and normal controls, and showed positive correlation with TNFα mRNA expression. The protein level of nuclear HDAC1 was higher in RA synovial tissue compared with OA synovial tissue. Stimulation with TNFα significantly increased the nuclear HDAC activity and HDAC1 mRNA expression at 24 hours and HDAC1 protein expression at 48 hours in RASFs.Conclusions: Our results showed nuclear HDAC activity and expression of HDAC1 were significantly higher in RA than in OA synovial tissues, and they were upregulated by TNFα stimulation in RASFs. These data might provide important clues for the development of specific small molecule HDAC inhibitors. © 2010 Kawabata et al.
    licensee BioMed Central Ltd.

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  • Serum adipocyte fatty acid-binding protein is independently associated with coronary atherosclerotic burden measured by intravascular ultrasound Reviewed International journal

    Toru Miyoshi, Go Onoue, Atsushi Hirohata, Satoshi Hirohata, Shinichi Usui, Kazuyoshi Hina, Hiroshi Kawamura, Masayuki Doi, Kengo Fukushima Kusano, Shozo Kusachi, Yoshifumi Ninomiya

    ATHEROSCLEROSIS   211 ( 1 )   164 - 169   2010.7

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    Objectives: Adipocyte fatty acid-binding protein (A-FABP) has been shown to have an effect on insulin resistance, lipid metabolism, and atherosclerosis in animals. We therefore investigated the association between the serum A-FABP level and coronary atherosclerosis.
    Methods: One hundred twenty-five consecutive patients with coronary artery disease (CAD) were enrolled after coronary angiography. Plaque volume in non-culprit coronary arteries was determined using intravascular ultrasound and expressed as percent plaque volume (%PV). Voluntary blood donors (n = 120), matched for age and gender, served as controls. Serum levels of A-FABP, adiponectin, and inflammatory markers were measured by enzyme-linked immunosorbent assay.
    Results: The serum A-FABP level in CAD patients was significantly higher than in control subjects (median [25th-75th percentiles], 27.2 [20.5-37.1] ng/mL vs. 18.9 [14.6-24.5] ng/mL) (p &lt; 0.01). Serum A-FABP showed 0.74 of the area under the curve in the receiver operating characteristic curve for the detection of CAD, with 76% specificity and 65% sensitivity with a cut-off value of 20.1 ng/mL. Further, in CAD patients, serum A-FABP had a significant correlation with %PV in all subjects (r = 0.33, p &lt; 0.01). Serum A-FABP was positively correlated with the body mass index, serum interleukin-6 and high-sensitive CRP, and negatively correlated with HDL-cholesterol and serum adiponectin in CAD patients. Stepwise regression analysis revealed that serum A-FABP was independently associated with %PV.
    Conclusion: Increased serum A-FABP was significantly associated with a greater coronary plaque burden. Our findings revealed that the measurement of serum A-FABP could be utilized for the evaluation of the extent of coronary atherosclerosis. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

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  • Type IV Collagen Induces Expression of Thrombospondin-1 that is Mediated by Integrin alpha 1 beta 1 in Astrocytes Reviewed International journal

    Tomoko Yonezawa, Shunji Hattori, Junko Inagaki, Masae Kurosaki, Tomoyuki Takigawa, Satoshi Hirohata, Toru Miyoshi, Yoshifumi Ninomiyai

    GLIA   58 ( 7 )   755 - 767   2010.5

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    Following brain injury, thrombospondin-1 (TSP-1) is involved in angiogenesis and synaptic recovery. In this study, we used a cold injury-model and found that TSP-1 mRNA was markedly upregulated after brain injury. Immunohistochemistry showed that TSP-1 was upregulated in both the core of the lesion and in the perilesional area of injured brain tissue. Numerous astrocytes immunopositive for glial fibrillary acidic protein (GFAP) were found in the perilesional area, and TSP-1 was also expressed in almost all astrocytes surrounding blood vessels at 4 days after injury. Next, we examined the influence of vascular basement membrane components on TSP-1 expression. When astrocytes were cultured on type IV collagen, TSP-1 was significantly upregulated compared with the expression when cells were grown on lamin, fibronectin, or poly-L-lysine. This increase occurred exclusively when astrocytes were grown on the native form of type IV collagen but not on the heat-denatured form or the non-collagenous 1 domain. Further, integrin alpha 1 and beta 1 mRNAs were upregulated concomitantly with GFAP mRNA, and integrin alpha 1 protein was localized to the endfeet of astrocytes that surrounded blood vessels in the injured brain. Using function-blocking antibodies, we found that the effect of type IV collagen was attributed to integrin alpha 1 beta 1 in primary astrocytes. Collectively, our results suggest that vascular basement membrane components substantially impact gene expression in astrocytes during brain tissue repair. (C) 2010 Wiley-Liss, Inc.

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  • Impact of Olmesartan on Progression of Coronary Atherosclerosis A Serial Volumetric Intravascular Ultrasound Analysis From the OLIVUS (Impact of OLmesarten on progression of coronary atherosclerosis: evaluation by IntraVascular UltraSound) Trial Reviewed International journal

    Atsushi Hirohata, Keizo Yamamoto, Toru Miyoshi, Kunihiko Hatanaka, Satoshi Hirohata, Hitoshi Yamawaki, Issei Komatsubara, Masaaki Murakami, Eiki Hirose, Shinji Sato, Keisuke Ohkawa, Makoto Ishizawa, Hirosuke Yamaji, Hiroshi Kawamura, Shozo Kusachi, Takashi Murakami, Kazuyoshi Hina, Tohru Ohe

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   55 ( 10 )   976 - 982   2010.3

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    Objectives The aim of this study was to evaluate the impact of olmesartan on progression of coronary atherosclerosis.
    Background Prior intravascular ultrasound (IVUS) trial results suggest slowing of coronary atheroma progression with some medicines but have not shown convincing evidence of regression with angiotension-II receptor blocking agents.
    Methods A prospective, randomized, multicenter trial-OLIVUS (Impact of OLmesartan on progression of coronary atherosclerosis: evaluation by IntraVascular UltraSound)-was performed in 247 stable angina pectoris patients with native coronary artery disease. When these patients underwent percutaneous coronary intervention for culprit lesions, IVUS was performed in their nonculprit vessels (without angiographically documented coronary stenosis [&lt;50%]). Patients were randomly assigned to receive 10 to 40 mg of olmesartan or control and treated with a combination of beta-blockers, calcium channel blockers, diuretics, nitrates, glycemic control agents, and/or statins per physician's guidance. Serial IVUS examinations (baseline and 14-month follow-up) were performed to assess coronary atheroma volume. Volumetric IVUS analyses included lumen, plaque, vessel volume, percent atheroma volume (PAV), percent change in total atheroma volume (TAV) and PAV.
    Results Patient characteristics and blood pressure control were identical between the 2 groups. However, follow-up IVUS showed significantly decreased TAV and percent change in PAV in the olmesartan group (5.4% vs. 0.6% for TAV and 3.1% vs. -0.7% for percent change in PAV, control vs. olmesartan, p &lt; 0.05 for all).
    Conclusions These observations suggest a positive role in a potentially lower rate of coronary atheroma progression through the administration of olmesartan, an angiotension-II receptor blocking agent, for patients with stable angina pectoris. (J Am Coll Cardiol 2010; 55: 976-82) (C) 2010 by the American College of Cardiology Foundation

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  • Regulation of cellular immunity prevents Helicobacter pylori-induced atherosclerosis Reviewed

    K. Ayada, K. Yokota, K. Hirai, K. Fujimoto, K. Kobayashi, H. Ogawa, K. Hatanaka, S. Hirohata, T. Yoshino, Y. Shoenfeld, E. Matsuura, K. Oguma

    LUPUS   18 ( 13 )   1154 - 1168   2009.11

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    Helicobacter pylori (H. pylori) is a predominant pathogen that causes not only gastroduodenal diseases but also extra-alimentary tract diseases. In this study, we demonstrated that H. pylori infection promoted atherogenesis in heterozygous apoe(+/-) ldlr(+/-) mice. The male mice were fed with high fat diet from the age of 6 weeks. At the age of 16 weeks, development of atherosclerotic lesions was observed in the H. pylori-infected mice, and it seemed to be associated with an elevation of Th1-immune response against H. pylori origin-heat shock protein 60 (Hp-HSP60) and an increment of transendothelial migration of T cells. Subcutaneous immunisation with Hp-HSP60 or H. pylori eradication with antibiotics significantly reduced the progression of atherosclerosis, accompanied by a decline of Th1 differentiation and reduction of their chemotaxis beyond the endothelium. Thus, oral infection with H. pylori accelerates atherosclerosis in mice and the active immunisation with Hp-HSP60 or the eradication of H. pylori with antibiotics can moderate/prevent cellular immunity, resulting in a reduction of atherosclerosis. Lupus (2009) 18, 1154-1168.

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  • INCREASED mRNA EXPRESSION OF ADAMTS METALLOPROTEINASES IN METASTATIC FOCI OF HEAD AND NECK CANCER Reviewed International journal

    Kadir Demircan, Esra Gunduz, Mehmet Gunduz, Levent Bekir Beder, Satoshi Hirohata, Hitoshi Nagatsuka, Beyhan Cengiz, Mehmet Zeynel Cilek, Noboru Yamanaka, Kenji Shimizu, Yoshifumi Ninomiya

    HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK   31 ( 6 )   793 - 801   2009.6

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    Background. Although contribution of matrix metalloproteinases in cancer progression and dissemination is now well known, roles of recently discovered metalloproteinases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), in cancer development and progression remain mostly unknown.
    Methods. Here we examined the mRNA expression pattern of 6 members of ADAMTS aggrecanases (1, 4, 5, 8, 9, and 15) in primary head and neck cancer with and without metastasis by real-time reverse transcriptase-polymerase chain reaction.
    Results. Expression levels of ADAMTS mRNAs were lower in the majority of the primary tumors as compared with the controls, On the other hand, the expression levels of all of the ADAMTS mRNAs except ADAMTS4 were higher in the metastatic foci than in their corresponding primary tumors, which suggest that characteristics of the cancer cell population are different in the primary tumor and metastatic focus.
    Conclusion. Our findings suggest a metastasis model proposing accumulation of a subtype of cancer cells with high metastatic capacity within heterogenous primary tumor cell population. (c) 2009 Wiley Periodicals, Inc. Head Neck 31: 793-801, 2009

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  • ADAMTS1 Is a Unique Hypoxic Early Response Gene Expressed by Endothelial Cells Reviewed International journal

    Omer F. Hatipoglu, Satoshi Hirohata, M. Zeynel Cilek, Hiroko Ogawa, Toru Miyoshi, Masanari Obika, Kadir Demircan, Ryoko Shinohata, Shozo Kusachi, Yoshifumi Ninomiya

    JOURNAL OF BIOLOGICAL CHEMISTRY   284 ( 24 )   16325 - 16333   2009.6

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    ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is a member of the matrix metalloproteinase family. We have previously reported that ADAMTS1 was strongly expressed in myocardial infarction. In this study, we investigated whether hypoxia induced ADAMTS1 and investigated its regulatory mechanism. In hypoxia, the expression level of ADAMTS1 mRNA and protein rapidly increased in endothelial cells, but not in other cell types. Interestingly, the induction of ADAMTS1 by hypoxia was transient, whereas vascular endothelial growth factor induction by hypoxia in human umbilical vein endothelial cells (HUVEC) increased in a time-dependent manner. CoCl(2), a transition metal that mimics hypoxia, induced ADAMTS1 in HUVEC. The phosphatidylinositol 3-kinase inhibitor LY294002 dose-dependently inhibited the increase of ADAMTS1 mRNA expression in hypoxia. We characterized the promoter region of ADAMTS1, and the secreted luciferase assay system demonstrated that hypoxia induced luciferase secretion in the culture medium 4.6-fold in HUVEC. In the promoter region of ADAMTS1, we found at least three putative hypoxia-inducible factor (HIF) binding sites, and the chromatin immunoprecipitation assay revealed HIF-1 binding to HIF binding sites in the promoter region of ADAMTS1 under hypoxia. Recombinant ADAMTS1 protein promoted the migration of HUVEC under hypoxic conditions. In summary, we found that ADAMTS1 is transiently induced by hypoxia in endothelial cells, and its transcription is mediated by HIF-1 binding. Our data indicate that ADAMTS1 is a novel acute hypoxia-inducible gene.

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  • The 3'-untranslated region of ADAMTS1 regulates its mRNA stability. Reviewed

    Omer Faruk Hatipoglu, Satoshi Hirohata, Kursat Oguz Yaykasli, Mehmet Zeynel Cilek, Kadir Demircan, Ryoko Shinohata, Tomoko Yonezawa, Toshitaka Oohashi, Shozo Kusachi, Yoshifumi Ninomiya

    Acta medica Okayama   63 ( 2 )   79 - 85   2009.4

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    ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) is an inflammatory-induced gene. We have previously reported that ADAMTS1 was strongly but transiently expressed in the infarcted heart. In this study, we investigated whether a 3'-untranslated region (UTR) affects the mRNA stability of this gene. When stimulated with tissue necrosis factor (TNF)-alpha, the expression level of ADAMTS1 mRNA rapidly increased, but the induction of ADAMTS1 mRNA peaked at 6h after stimulation, after which the expression levels of ADAMTS1 mRNA decreased. The 3'-UTR ADAMTS1 mRNA contains multiple adenine and uridine-rich elements, suggesting that the 3'-UTR may regulate gene stability. The addition of actinomycin D, an RNA synthesis inhibitor, demonstrated the decay of induced ADAMTS1 mRNA by TNF-alpha. Furthermore, a region containing multiple AUUUA motifs within the ADAMTS1 3'-UTR destabilized transfected Enhanced Green Fluorescence Protein (EGFP) mRNA expression. These results demonstrated that the ADAMTS1 3'-UTR may regulate the expression of ADAMTS1 mRNA.

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  • ADAMTS9 activation by interleukin 1 beta via NFATc1 in OUMS-27 chondrosarcoma cells and in human chondrocytes. Reviewed International journal

    Kursat Oguz Yaykasli, Toshitaka Oohashi, Satoshi Hirohata, Omer Faruk Hatipoglu, Kiichi Inagawa, Kadir Demircan, Yoshifumi Ninomiya

    Molecular and cellular biochemistry   323 ( 1-2 )   69 - 79   2009.3

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    ADAMTS9 is a member of the disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) genes, with aggrecan-degrading activity. It has also been characterized to be reactive and highly activated ADAMTS by IL-1 beta in both chondrosarcoma cells and human chondrocytes (Demircan et al. Arthritis Rheum 52:1451-1460, 2005). In order to understand the regulation of ADAMTS9 gene expression a functional 3.0 kb human ADAMTS9 promoter has been cloned and characterized. A sequence analysis of the promoter revealed the presence of putative binding sites for Nuclear Factor of Activated T cells (NFAT), which is commonly found in the ADAMTS4 and ADAMTS5 promoters. NFATc1 was up-regulated in an activated form by IL-1 beta in human chondrocytes. The IL-1 beta inducible ADAMTS9 expression was inhibited by NFAT inhibitors, FK506 and 11Arg (11R)-VIVIT. Furthermore, direct binding of NFATc1 on distal and proximal promoters of ADAMTS9 was demonstrated by a chromatin immunoprecipitation assay. Promoter-reporter assays supported those results. These findings may provide a better understanding of the regulation of ADAMTS9 expression induced by inflammatory cytokines.

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  • siRNA silencing reveals role of vascular cell adhesion molecule-1 in vascular smooth muscle cell migration Reviewed International journal

    Erik J. Petersen, Toru Miyoshi, Zuobiao Yuan, Satoshi Hirohata, Jin Zhong Li, Weibin Shi, John F. Angle

    ATHEROSCLEROSIS   198 ( 2 )   301 - 306   2008.6

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    Vascular cell adhesion molecule-1 (VCAM-1) is an adhesion molecule expressed by endothelial cells for recruitment of leukocytes during inflammation. It is also abundantly expressed by smooth muscle cells in atherosclerotic lesions and in injured arteries. In this study, we examined the role of VCAM-1 in smooth muscle cell migration. Smooth muscle cells were isolated from the aorta of C57BL/6 mice and transfected with short interfering RNAs (siRNAs) targeting VCAM-1. Inhibition on VCAM-1 expression by siRNAs was assessed by Western blot analysis, RT-PCR and by measuring soluble VCAM-1 concentrations in the incubation medium. One siRNA that showed greater suppression on VCAM-1 expression was used for migration assay. A single scratch wound was made on 70% confluent cells and cells migrated from wounded monolayer were counted 24 and 48 h after injury. Treatment with VCAM-1 siRNA resulted in a significant reduction in the number of migrated cells. This siRNA also exhibited a minor effect on smooth muscle cell proliferation. Thus, our findings indicate that VCAM-1 is necessary for the migration of smooth muscle cells and interfering VCAM-1 expression could be an effective approach to prevention and treatment of atherosclerosis and restenosis. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

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  • Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen anti body-induced arthritis mouse model Reviewed

    Y. Nasu, K. Nishida, S. Miyazawa, T. Komiyama, Y. Kadota, N. Abe, A. Yoshida, S. Hirohata, A. Ohtsuka, T. Ozaki

    OSTEOARTHRITIS AND CARTILAGE   16 ( 6 )   723 - 732   2008.6

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    Objective: To investigate the effect of the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), on joint inflammation and cartilage degeneration in a collagen antibody-induced arthritis (CAIA) mouse model.
    Methods: CAIA mice were given daily subcutaneous injections of various concentrations of TSA (0, 0.5, 1.0, and 2.0 mg/kg) and various parameters were monitored for 14 days. On Day 15, the hind paws were examined histologically. To investigate the effects of TSA on the expressions of matrix metal lop roteinase (MMP)-3, MMP-13, tissue inhibitor of MMP-1 (TIMP-1), and acetyl-H4 by chondrocytes, another group of mice was sacrificed on Day 6. In vitro direct effect of TSA was examined by real-time PCR for mRNA of type II collagen, aggrecan, MMP-3, and MMP-13 in murine chondrogenic ATDC5 cells after pro-inflammatory cytokine stimulation.
    Results: In the TSA-treated group, clinical arthritis was significantly ameliorated in a dose-dependent manner. The severity of synovial inflammation and the cartilage destruction score were significantly lower in the TSA 2.0 mg/kg group compared to the other TSA-treated groups. On immunohistochemistry, the number of MMP-3 and MMP-13-positive chondrocytes was significantly lower in the TSA 2.0 mg/kg group than in the control group. In contrast, the number of TIMP-II-positive cells and acetyl-histone H4-positive cells was significantly higher in the TSA 2.0 mg/kg group than in the control group. TSA suppressed interleukin 1-beta and tumor necrosis factor-a-stimulated up-regulation of MMP-3, but not MMP-13 mRNA expression by ATDC5.
    Conclusion: The systemic administration of TSA ameliorated synovial inflammation in CAIA mice. Subsequently cartilage destruction was also suppressed by TSA, at least in part, by modulating chondrocyte gene expression. (C) 2007 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

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  • Association of augmentation index of radial pressure wave form with diurnal variation pattern of blood pressure in untreated patients with essential hypertension Reviewed International journal

    Ryoko Shinohata, Takaaki Nakatsu, Yoko Yuki, Aya Nishitani, Keiichi Mashima, Shinji Toyonaga, Hiroko Ogawa, Satoshi Hirohata, Shinichi Usui, Tomoki Kitawaki, Shozo Kusachi

    JOURNAL OF HYPERTENSION   26 ( 3 )   535 - 543   2008.3

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    Objectives The augmentation index of the radial pulse wave has been reported to be a sensitive aortic stiffness marker in relatively young but not in older individuals. We studied the relationship between augmentation index and the diurnal blood pressure profiles.
    Patients and methods Twenty-four-hour ambulatory blood pressure monitoring was performed in 90 untreated patients with uncomplicated essential hypertension. The patients were classified into four groups: dippers, extreme dippers, nondippers, and risers. Augmentation index was calculated as the percentage of the second systolic peak relative to the first systolic peak.
    Results No significant differences in the averaged whole 24-h systolic or diastolic blood pressure were observed in the whole set of patients or in subgroup patients with age 60 years or under. In the whole set of patients (58.7 +/- 12.9 years), there were significant differences in augmentation index between patients with abnormal (other than dippers) and normal diurnal blood pressure profiles (dippers). In subgroup patients with age 60 years or below (49.1 +/- 9.1 years, n = 48), the abnormal diurnal blood pressure profile group showed significantly higher augmentation index (89.6 +/- 10.3%) than dippers (80.5 +/- 11.8%). The area under the curve in the receiver operating characteristics curve for distinguishing between dippers than other dippers was 0.73 (P &lt; 0.01). Multivariate analysis demonstrated that abnormal diurnal blood pressure profile was independently associated with increase in augmentation index. In contrast, these relationships were not significant in the over 60 years subgroup patients (69.8 +/- 5.6 years old, n = 42).
    Conclusions The present study revealed that augmentation index was associated with dipping blood pressure patterns in untreated hypertensive patients aged 60 years or younger. Augmentation index determination would be useful for initial assessment in connection with possible abnormal diurnal blood pressure variability in patients with age 60 years or younger.

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  • Serum interferon-gamma-inducible protein 10 level was increased in myocardial infarction patients, and negatively correlated with infarct size Reviewed International journal

    Kazuya Koten, Satoshi Hirohata, Toru Miyoshi, Hiroko Ogawa, Shinichi Usui, Ryoko Shinohata, Mutsumi Iwamoto, Tomoki Kitawaki, Shozo Kusachi, Kosaku Sakaguchi, Tohru Ohe

    CLINICAL BIOCHEMISTRY   41 ( 1-2 )   30 - 37   2008.1

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    Objectives: We examined the serum levels of interferon-gamma-inducible protein 10 (IP-10), an inflammation-induced chemokine, in acute myocardial infarction (AMI).
    Design and methods: The subjects were 33 AMI patients, 20 stable angina pectoris patients (AP) and 20 normal subjects. In AMI patients, blood samples were collected before percutaneous coronary intervention (PCI) and on days 3, 7 and 28.
    Results: Patients with AMI showed significantly higher serum IP-10 levels (137.5 +/- 79.8 pg/mL) than control subjects (91.2 +/- 40.1 pg/mL) and patients with AP (93.3 +/- 41.1 pg/mL). The serum IP-10 level before PCI was negatively correlated with infarct size, as indicated by cumulative release of creatine kinase (CK) and peak CK and its isoenzyme CK-MB Stepwise multiple regression analysis revealed that the serum IP-10 level before PCI was an independent predictor of cumulative CK release.
    Conclusions: The serum IP-10 level was increased in AMI, and a higher level of serum IP- 10 before PCI may be informative regarding infarct size. (c) 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

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  • Antibodies against heat shock protein 60 derived from Helicobacter pylori: Diagnostic implications in cardiovascular disease Reviewed

    Tomoyuki Okada, Kiyoshi Ayada, Shinichi Usui, Kenji Yokata, Jinhua Cui, Yoshiro Kawahara, Tomoki Inaba, Satoshi Hirohata, Motowo Mizuno, Daisuke Yamamoto, Shozo Kusachi, Eiji Matsuura, Keiji Oguma

    JOURNAL OF AUTOIMMUNITY   29 ( 2-3 )   106 - 115   2007.9

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    Immune responses against heat shock protein 60 (HSP60) of pathogen-origin are thought to be defensive events which, due to molecular mimicry, misdirect to a human counterpart. Therefore, atherosclerosis may be serologically predicted by anti-HSP60 antibodies (Abs). In the present study, we analyzed the clinical prevalence of the serum IgG Abs against Helicobacter pylori (Hp)-derived HSP60 (Hp-HSP60) or its peptide fragments in patients with cardiovascular disease (CVD; n = 250), as compared to those in age- and gender-matched non-CVD patients (n = 293). Anti-Hp cell lysate Abs frequently appeared in Hp-infected patients who were not associated with CVD. In contrast, Abs against the particular amino acid sequence Hp-HSP60(II3) (II3 region, Glu(141)-Leu(160), in Hp-HSP60) predominantly appeared in CVD patients, as well as IgG anti-human HSP60 (Hu-HSP60(w)). Furthermore, neither titer of anti-Hp-HSP60(113) nor anti-Hu-HSP60(w) Abs was correlated with the levels of high sensitivity C-reactive protein (hsCRP). This data strongly suggested that IgG anti-Hp-HSP60(II3) Abs cross-reacted with Hu-HSP60(w) were independent diagnostic markers relevant to CVD. Further, the 20 amino acid residues (Glu(141)-Leu(160)) might be predominant CVD-associated epitopes that induce anti-Hu-HSP60 auto-Abs, whose location was predicted in the tertiary structure of Hu-HSP60. (c) 2007 Elsevier Ltd. All rights reserved.

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  • Use of plasma B-Type natriuretic peptide level to identify asymptomatic hypertensive patients with abnormal diurnal blood pressure variation profiles: nondippers, extreme dippers, and risers Reviewed International journal

    Takaaki Nakatsu, Ryoko Shinohata, Keiichi Mashima, Yoko Yuki, Aya Nishitani, Shinji Toyonaga, Hiroko Ogawa, Satoshi Hirohata, Shinichi Usui, Shozo Kusachi

    HYPERTENSION RESEARCH   30 ( 7 )   651 - 658   2007.7

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    We examined the relationship between plasma B-type natriuretic peptide (BNP) level and diurnal variability pattern of blood pressure (BP). Twenty-four-hour ambulatory BP monitoring was performed in 98 patients with asymptomatic essential hypertension, and the patients were classified into four groups according to their circadian BP variation profiles: dippers (n=29), nondippers (n=36), extreme dippers (n=19), and risers (n=14). Plasma BNP was measured by enzyme immunoassay. Based on the distribution pattern of BNP values, the values were analyzed after logarithmic transformation. Significant differences in plasma BNP levels among the types of circadian BP variations were demonstrated by analysis of variance (p &lt; 0.0005). Nondippers and risers showed significantly higher plasma BNP levels (mean [range: -1 SD and +1 SD]: 16.1 [6.3, 41.6) pg/mL and 29.2 [15.9, 53.4] pg/mL, respectively) than dippers (8.4 [3.7, 19.1] pg/mL). The area under the receiver operating characteristics curve for distinguishing patients with abnormal circadian BP variation from those with normal variation was 0.72, indicating that plasma BNP levels were useful for distinguishing between these patients. Specificity of 69% and sensitivity of 72% were obtained with a cut-off value of 10.5 pg/mL (log plasma BNP, 1.02) for distinguishing the abnormal diurnal BP profile group from the normal group. In conclusion, hypertensive patients with abnormal diurnal BP variation patterns (nondippers, extreme dippers, and risers) showed higher plasma BNP levels than those with normal circadian BP variation (dippers). Plasma BNP level is clinically useful for the identification of hypertensive patients who have abnormal circadian BP variability, which increases the risk of cardiovascular events.

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  • Thrombospondin-1 is induced in rat myocardial infarction and its induction is accelerated by ischemia/reperfusion Reviewed International journal

    S Sezaki, S Hirohata, A Iwabu, K Nakamura, K Toeda, T Miyoshi, H Yamawaki, K Demircan, S Kusachi, Y Shiratori, Y Ninomiya

    EXPERIMENTAL BIOLOGY AND MEDICINE   230 ( 9 )   621 - 630   2005.10

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    Thrombospondin-1 (TSP-1) is a multifunctional, rapid-turnover matricellular protein. Recent studies demonstrated that TSP-1 has a role in regulating inflammatory reactions. Myocardial infarction (MI) is associated with an inflammatory response, ultimately leading to healing and scar formation. In particular, an enhanced inflammatory reaction and a massive accumulation of monocytes/macrophages is seen with reperfusion after MI. To examine the role of TSP-1 in MI, we isolated rat TSP-1 complementary DNA (cDNA) and analyzed the level and distribution of the mRNA expression. In infarcted rat hearts, TSP-1 mRNA increased markedly at 6 and 12 hrs after coronary artery ligation (27.97 +/- 3.40-fold and 22.77 +/- 1.83-fold, respectively, compared with sham-operated hearts). Western blot analysis revealed that TSP-1 protein was transiently induced in the infarcted heart. Using in situ hybridization analysis, TSP-1 mRNA signals were observed in the infiltrating cells at the border area of infarction. We then examined the effect of ischemia/reperfusion (I/R) on TSP-1 mRNA induction in the rats with infarcted hearts. Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) demonstrated that I/R enhanced the TSP-1 mRNA expression approximately 4-fold, as compared with the level in the permanently ligated heart. Finally, we examined the effect of TSP-1 on proinflammatory cytokine release in mononuclear cells. The releases of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) from human mononuclear cells were enhanced by TSP-1 in a dose-dependent manner. Thus, the immediate and marked increase of TSP-1 expression suggests that TSP-1 has an inflammatory-associated role in MI.

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  • Therapeutic efficacy of PUMA for malignant glioma cells regardless of p53 status Reviewed International journal

    H Ito, T Kanzawa, T Miyoshi, S Hirohata, S Kyo, A Iwamaru, H Aoki, Y Kondo, S Kondo

    HUMAN GENE THERAPY   16 ( 6 )   685 - 698   2005.6

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    Replacement of the p53 tumor suppressor gene is a rational approach to the management of malignant gliomas because p53 is frequently mutated or inactivated in these cancers. Major weaknesses of this approach are that malignant gliomas are mixtures of cells with wild- type and mutant p53, and that tumor cells exhibiting wildtype p53 are resistant to p53 gene transfer. An effective alternative is needed to overcome these difficulties. p53-upregulated modulator of apoptosis ( PUMA) was identified as a p53- inducible proapoptotic molecule. Our purpose was to elucidate a role for PUMA in p53 gene therapy and to investigate whether PUMA is an efficient substitute for p53 in cancer therapy. We demonstrated that PUMA was upregulated in mutant p53 malignant glioma cells (U373-MG and T98G) undergoing apoptosis but was not upregulated in apoptosis-resistant wild- type p53 malignant glioma cells (U87-MG and D54) after adenoviral transfer of p53. Overexpression of PUMA resulted in massive apoptosis associated with mitochondrial damage and caspase-3 activation in all tumor cells tested. Use of the human telomerase reverse transcriptase ( hTERT) promoter system induced apoptosis only in malignant glioma cells with telomerase activity, while sparing normal cells lacking telomerase. The ability of PUMA to induce apoptosis was greater than that of caspase-6 or caspase-8 transfer, using the same system. Moreover, exogenous expression of PUMA under the hTERT promoter system significantly suppressed the growth of subcutaneous U87-MG tumors in nude mice and did not induce apoptosis in surrounding nontumor tissues. These results indicate that PUMA, which is regulated under a tumor-specific expression system such as the hTERT promoter, may be better than p53 as a therapeutic tool for malignant gliomas.

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  • ADAMTS-9 is synergistically induced by interleukin-1 beta and tumor necrosis factor alpha in OUMS-27 chondrosarcoma cells and in human chondrocytes Reviewed International journal

    K Demircan, S Hirohata, K Nishida, OF Hatipoglu, T Oohashi, T Yonezawa, SS Apte, Y Ninomiya

    ARTHRITIS AND RHEUMATISM   52 ( 5 )   1451 - 1460   2005.5

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    Objective. To compare induction of the aggrecanases (ADAMTS-1, ADAMTS-4, ADAMTS-5, ADAMTS-8, ADAMTS-9, and ADAMTS-15) by interleukin-1&beta; (IL-1&beta;) and tumor necrosis factor a (TNF&alpha;) in chondrocyte-like OUMS-27 cells and human chondrocytes, and to determine the mechanism of induction of the most responsive aggrecanase gene.
    Methods. OUMS-27 cells were stimulated for different periods of time and with various concentrations of IL-1&beta; and/or TNFa. Human chondrocytes obtained from osteoarthritic joints and human skin fibroblasts were also stimulated with IL-1&beta; and/or TNF&alpha;. Total RNA was extracted, reverse transcribed, and analyzed by quantitative real-time polymerase chain reaction and Northern blotting. ADAMTS-9 protein was examined by Western blotting, and the role of the MAPK signaling pathway for ADAMTS9 induction in IL-1&beta;-stimulated OUMS-27 cells was investigated.
    Results. IL-1&beta; increased messenger RNA (mRNA) levels of ADAMTS4, ADAMTS5, and ADAMTS9 but not ADAMTS1 and ADAMTS8. The fold increase for ADAMTS9 mRNA was greater than that for mRNA of the other aggrecanase genes. The increase of ADAMTS9 mRNA by IL-1&beta; stimulation was greater in chondrocytes than in fibroblasts. The combination of IL-1&beta; and TNF&alpha; had a synergistic effect, resulting in a considerable elevation in the level of ADAMTS9 mRNA. ADAMTS-9 protein was also induced in IL-1&beta;-stimulated OUMS-27 cells. The MAPK inhibitors SB203580 and PD98059 decreased ADAMTS9 upregulation in OUMS-27 cells.
    Conclusion. ADAMTS9 is an IL-1&beta;- and TNF&alpha;-inducible gene that appears to be more responsive to these proinflammatory cytokines than are other aggrecanase genes. Furthermore, these cytokines had a synergistic effect on ADAMTS9. Together with the known ability of ADAMTS-9 to proteolytically degrade aggrecan and its potential to cleave other cartilage molecules, the data suggest that ADAMTS-9 may have a pathologic role in arthritis.

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  • Suppression of chondrosarcoma cells by 15-deoxy-Delta (12,14)-prostaglandin J(2) is associated with altered expression of Bax/Bcl-xL and p21 Reviewed International journal

    ZN Shen, K Nishida, H Doi, T Oohashi, S Hirohata, T Ozaki, A Yoshida, Y Ninomiya, H Inoue

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   328 ( 2 )   375 - 382   2005.3

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    We previously reported that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), the most potent agonist for peroxisome proliferator-activated receptor gamma (PPARgamma), induces apoptosis of human chondrosarcoma cell line OUMS-27. The current study aimed to explore the mechanism of 15d-PGJ(2)-induced apoptosis and inhibition of cell proliferation in OUMS-27 cells. The preliminary results of cDNA microarray analysis showed the down-regulation of anti-apoptotic Bcl-xL and up-regulation of pro-apoptotic Bax in the process of 15d-PGJ2-induced apoptosis. These changes were further confirmed at mRNA and protein levels by RT-PCR and Western blot analysis, respectively. Among cyclin-dependent kinase inhibitors, p21 was induced and up-regulated by 15d-PGJ2, but p 16 and p27 were not changed, suggesting that the involvement of p21 in inhibition of cell proliferation. Activation of caspase-3 by 15d-PGJ2 was partly, but not completely, blocked by PPARgamma antagonist (GW9662) suggesting the 15d-PGJ2 exerted its effect by PPARgamma-dependent and -independent pathways. Interestingly, immunohistochemical study on human chondrosarcoma samples revealed that Bcl-xL is frequently expressed by tumor cells. The results of the current study suggest that the potential ability of 15d-PGJ2 in regulation of cell cycle and inhibition of Bcl-xL expression might be beneficial in the development of novel pharmacological agents for chondrosarcoma. (C) 2005 Elsevier Inc. All rights reserved.

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  • Time-dependent changes in plasma osteopontin levels in patients with anterior-wall acute myocardial infarction after successful reperfusion: Correlation with left-ventricular volume and function International journal

    C Suezawa, S Kusachi, T Murakami, K Toeda, S Hirohata, K Nakamura, K Yamamoto, K Koten, T Miyoshi, Y Shiratori

    JOURNAL OF LABORATORY AND CLINICAL MEDICINE   145 ( 1 )   33 - 40   2005.1

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    Osteopontin Is a secreted extracellular-matrix glycoprotein that plays a role in the healing of remodeling tissue. We examined the relationship of plasma osteopontin levels with left-ventricular (LV) volume and function In 18 consecutive patients who underwent successful reperfusion after anterior-wall acute myocardial Infarction (AMI). The plasma osteopontin level was within the control range at admission (mean +/- SD 420 +/- 195 ng/mL), began to Increase on day 2 (935 +/- 464 ng/mL), and reached a maximum around day 3 (1139 482 ng/mL). The level remained high on days 4, 5, and 7 (similar to1000 ng/mL) and then decreased on day 14. Maximal plasma osteopontin levels and the difference between maximal and minimal levels were positively correlated with LV end-systolic volume index (r = .58, P &lt; .05; and r = .65, P &lt; .01, respectively) and negatively correlated with LV election fraction (r = -.52, P &lt; .05; and r = -.60, P &lt; .01, respectively). The area under the curve of plasma osteopontin levels for 14 days after AMI was significantly correlated with LV end-systolic volume index (r = .66, P &lt; .01), LV end-diastolic volume index (r = .50, P &lt; .05), and LV ejection fraction (r = -.55, P &lt; .05). In subgroup patients with the same area of risk for myocardial infarction (ie, responsible lesions located at the same proximal left anterior descending coronary artery), essentially the some or a closer relationship between plasma osteopontin level and LV volume and function was noted. Plasma osteopontin levels were correlated substantially with plasma levels of high-sensitivity C-reactive protein (hsCRP) and weakly with serum creatine kinase release. In conclusion, the plasma level of osteopontin changes In a time-dependent fashion and Is correlated with LV volumes and function and associated substantially with the extent of the Inflammatory response Indicated by the plasma hsCRP level and weakly with Infarct size estimated on the basis of cardiac-enzyme release.

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  • Lp3/Hapln3, a novel link protein that co-localizes with versican and is coordinately up-regulated by platelet-derived growth factor in arterial smooth muscle cells International journal

    H Ogawa, T Oohashi, M Sata, Y Bekku, S Hirohataa, K Nakamura, T Yonezawa, S Kusachi, Y Shiratori, Y Ninomiya

    MATRIX BIOLOGY   23 ( 5 )   287 - 298   2004.8

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    Link proteins (LPs) belong to the link-module superfamily, which can stabilize and enhance the binding of lecticans to hyaluronan. We report here the identification and characterization of a novel rat link protein gene (Lp3/Hapln3). The deduced protein sequence shares the typical modular elements of link proteins and has an estimated mass of 39 kDa. Examination of the rat genomic DNA sequence revealed that Lp3/ Hapln3 and aggrecan genes were paired on chromosome 1q31. Another LP gene and the lectican gene were also paired at a different locus, as they are in the human and mouse genomes. Immunohistochemical analysis showed the prominent expression of Lp3/Hapln3 in the smooth muscle tissues of the vascular wall and gastrointestinal tract. Further comparative studies revealed that Lp3/Hapln3 was well co-localized with versican around the smooth muscle cells of blood vessels but not around endothelial cells. In vitro experiments using primary cultured rat arterial smooth muscle cells (ASMCs) demonstrated the coordinated up-regulation of Lp3/Hapln3 and versican by platelet-derived growth factor (PDGF). These data were supported by in vivo studies of a mechanical vascular injury model in mice. Altogether, our results suggest that Lp3/Hapln3 is involved, together with versican and hyaluronan, in the formation of the pericellular matrix of vascular smooth muscle cells. (C) 2004 Elsevier B.V./International Society of Matrix Biology. All rights reserved.

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  • Increased expression of dermatopontin mRNA in the infarct zone of experimentally induced myocardial infarction in rats: comparison with decorin and type I collagen mRNAs International journal

    S Takemoto, T Murakami, S Kusachi, A Iwabu, S Hirohata, K Nakamura, S Sezaki, J Hayashi, C Suezawa, Y Ninomiya, T Tsuji

    BASIC RESEARCH IN CARDIOLOGY   97 ( 6 )   461 - 468   2002.11

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    Objectives Dermatopontin, a 22 kDa extracellular matrix (ECM) protein, has been shown to interact with other ECM components, especially decorin, and to regulate ECM formation. We examined dermatopontin mRNA expression in the myocardial infarct zone. Methods The cDNA encoding the rat dermatopontin was cloned by RT-PCR based on screening results from the Expressed Sequence Tag(TM) database. The dermatopontin mRNA expression was examined in the infarct zone after experimentally induced myocardial infarction in rats by the methods of Northern blotting and in situ hybridization. The expression of dermatopontin mRNA was compared to that of decorin and type I collagen mRNAs. Results The isolated clone contained a 609 bp cDNA insert containing a complete open reading frame encoding 202 amino acids. The rat dermatopontin cDNA showed high homology to human and mouse counterparts (&gt;96%). Northern blotting demonstrated that dermatopontin mRNA expression did not markedly increase on day 2, but was increased on days 7, 14 and 28 by 2.4-, 4.1- and 4.2-fold, respectively, compared to that in preligation hearts. Dermatopontin mRNA expression was regulated almost in parallel with decorin mRNA expression. In situ hybridization demonstrated mRNA signals for dermatopontin in macrophages and spindle-shaped mesenchymal cells (fibroblasts and myofibroblasts) located in the infarct interior zone around infarcted necrotic tissue on day 7. Coexpression of dermatopontin mRNA with decorin and type I collagen mRNAs was observed in spindle-shaped mesenchymal cells. Conclusions The present results demonstrated the time-dependent increase in the expression of dermatopontin mRNA in parallel with that of decorin mRNA in the infarct zone. Coexpression of dermatopontin mRNA with decorin and type I collagen mRNAs suggests that dermatopontin plays a role in ECM (fibrillar collagen matrix) reformation in the infarct along with decorin and type I collagen.

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  • Caspase-8 gene therapy using the human telomerase reverse transcriptase promoter for malignant glioma cells International journal

    T Komata, Y Kondo, T Kanzawa, H Ito, S Hirohata, S Koga, H Sumiyoshi, M Takakura, M Inoue, BP Barna, EM Germano, S Kyo, S Kondo

    HUMAN GENE THERAPY   13 ( 9 )   1015 - 1025   2002.6

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    Telomerase is a distinctive candidate for targeted gene therapy of malignant gliomas, because the vast majority of malignant gliomas express telomerase activity while normal brain tissues do not. Recently, we developed a telomerase-specific expression system of caspase-8 gene using the promoter of the human telomerase reverse transcriptase (hTERT) gene. However, the transcriptional activity of hTERT-181 promoter (a 181-base pair [bp] region upstream of the transcription start site) was relatively lower in malignant glioma cells than in other tumors such as prostate cancer cells. To establish the hTERT/caspase-8 construct as a novel therapy for malignant gliomas, we need to increase the transcriptional activity of the hTERT promoter in malignant glioma cells. In the present study, we demonstrate that the transcriptional activity of hTERT-378 promoter (a 378-bp region) was 2- to 40-fold higher in hTERT-positive malignant glioma cells (A172, GB-1, T98G, U87-MG, U251-MG, and U373-MG) than that of hTERT-181. We further demonstrate that by using the hTERT-378/caspase-8 construct, apoptosis was restricted to malignant glioma cells, and was not seen in astrocytes or fibroblasts lacking hTERT. Moreover, the growth of subcutaneously established U373-MG tumors in mice was significantly inhibited by seven daily intratumoral injections of hTERT-378/caspase-8 construct and its inhibitory effect persisted during 3 additional weeks without additional treatment. These results suggest that the telomerase-specific expression of caspase-8 under hTERT-378 promoter is a novel targeting approach for the treatment of telomerase-positive malignant gliomas.

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  • Punctin, a novel ADAMTS-like molecule, ADAMTSL-1, in extracellular matrix International journal

    S Hirohata, LW Wang, M Miyagi, L Yan, MF Seldin, DR Keene, JW Crabb, SS Apte

    JOURNAL OF BIOLOGICAL CHEMISTRY   277 ( 14 )   12182 - 12189   2002.4

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    Punctin (ADAMTSL-1) is a secreted molecule resembling members of the ADAMTS family of proteases. Punctin lacks the pro-metalloprotease and the disintegrin-like domain typical of this family but contains other ADAMTS domains in precise order including four thrombospondin type I repeats. Punctin is the product of a distinct gene on human chromosome 9p21-22 and mouse chromosome 4 that is expressed in adult skeletal muscle. His-tagged punctin expressed in stably transfected High-Five(TM) insect cells was purified to apparent homogeneity by Ni-chromatography of conditioned medium. The NH2 terminus is not blocked and has the sequence EEDRD and so forth as determined by Edman degradation, demonstrating signal peptidase processing. Recombinant epitope-tagged punctin has a calculated mass of 59,991 Da but exhibits major molecular species of 61970 +/- 6 Da and 62131 +/- 5 Da as measured by liquid chromatography electrospray mass spectrometry. Punctin is a glycoprotein based on carbohydrate staining and liquid chromatography electrospray mass spectrometry glycopeptide analysis. Glycosylation occurs at a single N-linked site as demonstrated by altered electrophoretic migration of punctin expressed in the presence of tunicamycin A. Punctin contains disulfide bonds based on antibody accessibility and electrophoretic migration under reducing versus nonreducing conditions. Rotary shadowing demonstrates that punctin is hatchet-shaped having a globular region attached to a short stem. In transfected COS-1 cells, punctin is deposited in the cell substratum in a punctate fashion and is excluded from focal contacts. Punctin is the first member of a novel family of ADAMTS-like proteins that may have important functions in the extracellular matrix.

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  • Procollagen II amino propeptide processing by ADAMTS-3 - Insights on dermatosparaxis

    RJ Fernandes, S Hirohata, JM Engle, A Colige, DH Cohn, DR Eyre, SS Apte

    JOURNAL OF BIOLOGICAL CHEMISTRY   276 ( 34 )   31502 - 31509   2001.8

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    The amino and carboxyl propeptides of procollagens I and Il are removed by specific enzymes as a prerequisite for fibril assembly. Null mutations in procollagen I N-propeptidase (ADAMTS-2) cause dermatosparaxis in cattle and the Ehlers-Danlos syndrome (dermatosparactic type) in humans by preventing proteolytic excision of the N-propeptide of procollagen I. We have found that procollagen II is processed normally in dermatosparactic nasal cartilage, suggesting the existence of another N-propeptidase(s). We investigated such a role for ADAMTS-3 in Swarm rat chondrosarcoma RCS-LTC cells, which fail to process the procollagen II N-propeptide. Stable transfection of RCS-LTC cells with bovine ADAMTS-2 or human ADAMTS-3 partially rescued the, processing defect, suggesting that ADAMTS-3 has procollagen II N-propeptidase activity. Human skin and skin fibroblasts showed 30-fold higher mRNA levels of ADAMTS-2 than ADAMTS-3, whereas ADAMTS-3 mRNA was 5-fold higher than ADAMTS-2 mRNA in human cartilage. We propose that both ADAMTS-2 and ADAMTS-3 process procollagen II, but ADAMTS-3 is physiologically more relevant, given its preferred expression in cartilage. The findings provide an explanation for the sparing of cartilage in dermatosparaxis and, perhaps, for the relative sparing of some procollagen I-containing tissues.

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  • Treatment of malignant glioma cells with the transfer of constitutively active caspase-6 using the human telomerase catalytic subunit (human telomerase reverse transcriptase) gene promoter

    T Komata, Y Kondo, T Kanzawa, S Hirohata, S Koga, H Sumiyoshi, SM Srinivasula, BP Barna, IM Germano, M Takakura, M Inoue, ES Alnemri, JW Shay, S Kyo, S Kondo

    CANCER RESEARCH   61 ( 15 )   5796 - 5802   2001.8

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    Because the apoptotic pathway is often disrupted in tumor cells, its genetic restoration is a very attractive approach for the treatment of tumors. To treat malignant gliomas with this approach, it would be preferred to restrict induction of apoptosis to tumor cells by establishing a tumor-specific expression system. Telomerase is an attractive target because the vast majority of malignant gliomas have telomerase activity whereas normal brain cells do not. Activation of telomerase is tightly regulated at the transcriptional level of the telomerase catalytic subunit [human telomerase reverse transcriptase, (hTERT)]. Therefore, we hypothesized that using a hTERT promoter-driven vector system, an apoptosis-inducible gene may be preferentially restricted to telomerase- or hTERT-positive tumor cells. In this study, we constructed an expression vector consisting of the constitutively active caspase-6 (rev-caspase-6) under the hTERT promoter (hTERT/rev-caspase-6) and then investigated its antitumor effect on malignant glioma cells. The rationale for using the rev-caspase-6 gene is because it induces apoptosis independent of the initiator caspases. We demonstrated that the hTERT/rev-caspase-6 construct induced apoptosis in hTERT-positive malignant glioma cells, but not in hTERT-negative astrocytes, fibroblasts, and alternative lengthening of telomeres cells. In addition, the growth of s.c. tumors in nude mice was significantly suppressed by the treatment with hTERT/rev-caspase-6 construct. The present results strongly suggest that the telomerase-specific transfer of the rev-caspase-6 gene under the hTERT promoter is a novel targeting approach for the treatment of malignant gliomas.

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  • FADD gene therapy using the human telomerase catalytic subunit (hTERT) gene promoter to restrict induction of apoptosis to tumors in vitro and in vivo

    S Koga, S Hirohata, Y Kondo, T Komata, M Takakura, M Inoue, S Kyo, S Kondo

    ANTICANCER RESEARCH   21 ( 3B )   1937 - 1943   2001.5

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    Gene transfer vectors will dramatically increase the safety and effectiveness of cancer gene therapy, if they could restrict expression of the therapeutic products to the target tumors. To realize such a tumor-targeting system, telomerase is one of the most promising candidates. It is because telomerase activity is detected in the vast majority of tumors, but not in most normal cells. Activation of telomerase is tightly regulated at the transcriptional level of the telomerase catalytic subunit (hTERT). Therefore, the use of the hTERT promoter-driven vector system could restrict the expression of therapeutic products to telomerase positive tumors. In this study, we constructed the expression vector of FADD gene with death domain afforded by the hTERT promoter (hTERT/FADD) and investigated its effect on tumors in vitro and in vivo. Transient transfection with the hTERT/FADD construct induced apoptosis in telomerase-positive tumor cells of wide range. In contrast, normal fibroblast cells without telomerase did not undergo apoptosis following the hTERT/FADD transfer. Furthermore, the growth of subcutaneous tumors in nude mice was significantly suppressed by the intratumoral injection of the hTERT/FADD construct (every day for one week) compared to the control (P &lt;0.0005). The findings described here indicate the high potentiality of a novel telomerase-specific gene therapy of tumors with telomerase.

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  • ADAMTS family - New extracellular matrix degrading enzyme

    S. Hirohata

    Seikagaku   73 ( 11 )   1333 - 1337   2001

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  • A novel telomerase-specific gene therapy: Gene transfer of caspase-8 utilizing the human telomerase catalytic subunit gene promoter

    Shoji Koga, Satoshi Hirohata, Yasuko Kondo, Tadashi Komata, Masahiro Takakura, Masaki Inoue, Saturo Kyo, Seiji Kondo

    Human Gene Therapy   11 ( 10 )   1397 - 1406   2000.7

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    Apoptosis is a genetically encoded cell death process and is a pathway that may be disrupted in tumor cells. Therefore, therapies that restore the ability to undergo apoptosis are promising for the treatment of tumor cells. We have demonstrated that the transfer of apoptosis-inducible genes inhibits the growth of tumors in vitro and in vivo through induction of apoptosis. However, to restrict induction of apoptosis to tumor cells, we need to explore a tumor-specific expression system of these genes. In the present study, we developed the telomerase-specific transfer system of apoptosis- inducible genes, utilizing the promoter of the human telomerase catalytic subunit (hTERT) gene. Approximately 90% of tumors have telomerase activity whereas most normal cells do not express the activity. These observations indicate that telomerase is a particularly attractive target for the tumor- specific expression system of vectors. We demonstrate here that by using the hTERT promoter-driven caspase-8 expression vector (hTERT/caspase-8), apoptosis is restricted to telomerase-positive tumor cells of wide range, and is not seen in normal fibroblast cells without telomerase activity. Furthermore, treatment of subcutaneous tumors in nude mice with the hTERT/caspase-8 construct inhibited tumor growth significantly because of induction of apoptosis (p &lt
    0.01). The telomerase-specific expression of apoptosis-inducible genes afforded by the hTERT promoter, therefore, may be a novel and promising targeting approach for the treatment of tumors with telomerase activity.

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  • Chromosomal mapping of Adam9, Adam15 and Adam21

    Michael F. Seldin, Satoshi Hirohata, Suneel S. Apte

    Matrix Biology   May;19(2):185-7 ( 2 )   185 - 187   2000.5

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    Adam9, Adam15 and Adam21, genes encoding members of the ADAM or MDC family of metalloproteases, have been mapped to mouse chromosomes 8, 1, and 12, respectively, using an interspecific cross. The mapping of these mouse loci and the extrapolated loci for their human orthologs may facilitate the mapping of diseases involving these genes. (C) 2000 Elsevier Science B.V./International Society of Matrix Biology.

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  • ADAM-TS8, a novel metalloprotease of the ADAM-TS family located on mouse chromosome 9 and human chromosome 11

    Katy E. Georgiadis, Satoshi Hirohata, Michael F. Seldin, Suneel S. Apte

    Genomics   Dec 1;62(2):312-5 ( 2 )   312 - 315   1999.12

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    A disintegrin-like and metalloprotease domain with thrombospondin type I modules (ADAM-TS) describes a novel family of zinc metalloendopeptidases. Its members have a common domain organization, which includes, typically, a pre- pro-metalloprotease domain, a disintegrin-like domain, and one or more thrombospondin-like (TS) modules. We describe here the complete primary structure of mouse ADAM-TS8, through cloning of Adamts8 cDNA. This novel member of the family contains two TS modules and is highly similar in sequence and domain organization to three other recently described gene products, ADAM-TS5, ADAM-TS6, and ADAM-TS7. Adamts8 is expressed at low levels throughout development and in adult mouse lung and heart. Through analysis of an interspecific backcross panel, we place the Adamts8 locus on mouse chromosome 9 at a consensus position of 11 cM and its human ortholog, recently reported as the METH2 gene, on human chromosome 11q25.

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  • ADAM-TS5, ADAM-TS6, and ADAM-TS7, novel members of a new family of zinc metalloproteases. General features and genomic distribution of the ADAM-TS family

    Tuna L. Hurskainen, Satoshi Hirohata, Michael F. Seldin, Suneel S. Apte

    Journal of Biological Chemistry   Sep 3;274(36):25555-63 ( 36 )   25555 - 25563   1999.9

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    We report the primary structure of three novel, putative zinc metalloproteases designated ADAM-TS5, ADAM-TS6, and ADAM-TS7. All have a similar domain organization, comprising a preproregion, a reprolysin-type catalytic domain, a disintegrin-like domain, a thrombospondin type-1 (TS) module, a cysteine-rich domain, a spacer domain without cysteine residues, and a COOH-terminal TS module. These genes are differentially regulated during mouse embryogenesis and in adult tissues, with Adamts5 highly expressed in the peri-implantation period in embryo and trophoblast. These proteins are similar to four other cognate gene products, defining a distinct family of human reprolysin-like metalloproteases, the ADAM-TS family. The other members of the family are ADAM-TS1, an inflammation-induced gene, the procollagen I/II amino-propeptide processing enzyme (PCINP, ADAM-TS2), and proteins predicted by the KIAA0366 and KIAA0688 genes (ADAMTS3 and ADAM-TS4). Individual ADAM-TS members differ in the number of COOH-terminal TS modules, and some have unique COOH-terminal domains. The ADAM-TS genes are dispersed in human and mouse genomes.

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  • Cloning of the human tissue inhibitor of metalloproteinase-4 gene (TIMP4) and localization of the TIMP4 and Timp4 genes to human chromosome 3p25 and mouse chromosome 6, respectively

    Timothy M. Olson, Satoshi Hirohata, Jean Ye, Kevin Leco, Michael F. Seldin, Suneel S. Apte

    Genomics   Jul 1;51(1):148-51 ( 1 )   148 - 151   1998.7

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    We have isolated genomic DNA containing the human tissue inhibitor of metalloproteinases-4 gene (TIMP4) and determined the structure of the exons comprising the gene. Like other members of the TIMP family, the TIMP-4 protein is encoded by five exons. These span 6 kb of genomic DNA, so that TIMP4 is similar in size to Timp1 but considerably smaller than TIMP2 and TIMP3. The exon-intron boundaries of TIMP4 are at locations very similar to those of the other TIMP genes, demonstrating the high degree of conservation of gene structure in this family. The human and mouse TIMP-4 genes map to comparable locations in the respective genomes, localizing to human chromosome 3p25 and mouse chromosome 6.

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  • Time-dependent alterations of serum levels of triple-helix domain and 7S domain of type IV collagen in patients with acute myocardial infarction after successful reperfusion: Limited relation to left ventricular ejection fraction

    Y Kajikawa, S Kusachi, J Kondo, Sano, I, K Yamamoto, S Hirohata, M Murakami, T Murakami, T Tsuji

    CLINICA CHIMICA ACTA   258 ( 2 )   241 - 247   1997.2

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    DOI: 10.1016/S0009-8981(96)06470-4

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  • Laminin α1, α2, α4 and β1 chain mRNA expression in mouse embryonic, neonatal, and adult hearts

    Satoshi Hirohata, Shozo Kusachi, Jun Kondo, Issei Sano, Masahiro Murakami, Masayuki Doi, Yoshifumi Ninomiya, Takao Tsuji

    Japanese Heart Journal   Mar;38(2):281-9 ( 2 )   281 - 289   1997

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    We examined the relative expression of laminin α1, α2, α4 and β1 chain genes in the heart of embryonic, neonatal and adult BALb/c mice. The reverse transcriptase-polymerase chain reaction was employed to determine the mRNA expression of these chains because of the relatively small amount of RNA extracted from rat embryonic hearts. Glyceraldehyde 3-phosphate dehydrogenase and β-actin were used as internal controls. Among the hearts examined, a relatively high expression of laminin α1 chain was observed in the embryonic hearts, while its expression was very weak in the neonatal and negligible in the adult hearts. Conversely, expression of laminin α2 chain was virtually not observed in the embryonic hearts, but this chain was expressed weakly in the neonatal and substantially in the adult hearts. Similar to laminin α1, laminin α4 was expressed in the embryonic hearts, while its expression was relatively weak in the neonatal and adult hearts. Laminin β1 was expressed in the hearts of mice at all stages examined. These results demonstrate that the laminin chain gene expression changes in the different developmental stages of the hearts of BALb/c mice.

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  • Time dependent alterations of serum matrix metalloproteinase-1 and metalloproteinase-1 tissue inhibitor after successful reperfusion of acute myocardial infarction

    Satoshi Hirohata, Shozo Kusachi, Masahiro Murakami, Takashi Murakami, Issei Sano, Tomoko Watanabe, Issei Komatsubara, Jun Kondo, Takao Tsuji

    Heart   78 ( 3 )   278 - 284   1997

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    Objective - To test the hypothesis that changes in serum matrix metalloproteinase-1 (MMP-1) and tissue inhibitors of metalloproteinase-1 (TIMP-1) after acute myocardial infarction reflect extracellular matrix remodelling and the infarct healing process. Patients - 13 consecutive patients with their first acute myocardial infarction who underwent successful reperfusion. Methods - Blood was sampled on the day of admission, and on days 2, 3, 4, 5, 7, 14, and 28. Serum MMP-1 and TIMP-1 were measured by one step sandwich enzyme immunoassay. Left ventricular volume indices were determined by left ventriculography performed four weeks after the infarct. Results - Serum concentrations of both MMP-1 and TIMP-1 changed over time. The average serum MMP-1 was more than 1 SD below the mean control values during the initial four days, increased thereafter, reaching a peak concentration around day 14, and then returned to the middle control range. Negative correlations with left ventricular end systolic volume index and positive correlations with left ventricular ejection fraction were obtained for serum MMP-1 on day 5, when it began to rise, and for the magnitude of rise in MMP-1 on day 5 compared to admission. Serum TIMP-1 at admission was more than 1 SD below the mean control value, and increased gradually thereafter, reaching a peak on around day 14. Negative correlations with left ventricular end systolic volume index and positive correlations with left ventricular ejection fraction were obtained for serum TIMP-1 on days 5 and 7, and for the magnitude of rise in TIMP-1 on days 5 and 7 compared to admission. Conclusions -Both MMP-1 and TIMP-1 showed significant time dependent alteration after acute myocardial infarction. Thus MMP-1 and TIMP-1 may provide useful information in evaluating the healing process as it affects left venticular remodelling after acute myocardial infarction.

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  • Tenascin expression in endomyocardial biopsy specimens in patients with dilated cardiomyopathy: Distribution along margin of fibrotic lesions

    Akiko Tamura, Shozo Kusachi, Kunio Nogami, Asami Yamanishi, Yutaka Kajikawa, Satoshi Hirohata, Takao Tsuji

    Heart   75 ( 3 )   295 - 300   1996

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    Objective - To examine the hypothesis that tenascin, an extracellular matrix glycoprotein, contributes to fibrotic changes in dilated cardiomyopathy. Methods - The localisation of tenascin in biopsy specimens of the hearts obtained from eight patients with dilated cardiomyopathy was examined using staining by the avidin-biotin-peroxidase complex method Results - (1) Perimysium and endomysium. Although positive staining for tenascin was observed in the enlarged perimysium and endomysium in all patients, moderately intense staining was characteristically observed near the replacement fibrotic lesions. In the narrow perimysium and endomysium of the myocardium not containing replacement fibrotic lesions, tenascin was not present, as in the control specimens. (2) Replacement fibrotic lesions. Non-homogeneous positive staining for tenascin was detected in all replacement fibrotic lesions examined. Intense tenascin deposition was observed in the peripheral portion of the replacement fibrotic lesions. The tenascin staining observed in the small replacement fibrotic lesions was more intense than that in the large lesions. Conclusions - Tenascin contributes to the development of the fibrotic changes seen in the dilated cardiomyopathic heart. Its characteristic location, specifically the distribution along the margin of the fibrosis, suggests that fibrotic change is a continuous process in hearts with dilated cardiomyopathy.

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  • Reperfusion hastens appearance and extent of distribution of type I collagen in infarct zone: Immunohistochemical study in rat experimental infarction

    S. Yamasaki, S. Kusachi, H. Moritani, J. Kondo, S. Hirohata, A. Tamura, T. Tsuji

    Cardiovascular Research   30 ( 5 )   763 - 768   1995

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    Background: The effects of reperfusion on time-dependent alteration of type I collagen have not been examined. Objectives: We compared the sequential changes in the appearance and distribution of type I collagen in reperfused infarct rat hearts to those in non-reperfused hearts. Methods: Using an experimental rat model of infarction, we performed immunohistochemical staining with a polyclonal antibody to type I collagen by the avidin-biotin-peroxidase method. Reperfusion was established after 2-h coronary ligation that produced complete necrosis of myocytes. Results: In reperfused hearts, type I collagen appeared in the peripheral zone of the infarct at day 2, which was 1 day earlier than in non-reperfused hearts. The extent of distribution of type I collagen in reperfused hearts was comparable to that observed approximately 1 day later in non-reperfused hearts. Conclusion: Reperfusion can accelerate collagen matrix formation compared with that in non-reperfused hearts after acute myocardial infarction.

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  • Basic characteristics between mechanomyogram and muscle force during twitch and tetanic contractions in rat skeletal muscles. Reviewed International journal

    Ikumi Sato, Shusei Yamamoto, Mai Kakimoto, Moe Fujii, Koki Honma, Shota Kumazaki, Mami Matsui, Hinako Nakayama, Sora Kirihara, Shang Ran, Satoshi Hirohata, Shogo Watanabe

    Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology   62   102627 - 102627   2022.2

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    The mechanomyogram (MMG) is a signal measured by various vibration sensors for slight vibrations induced by muscle contraction, and it reflects the muscle force during electrically induced-contraction or until 60%-70% maximum voluntary contraction, so the MMG is considered an alternative and novel measurement tool for muscle strength. We simultaneously measured the MMG and muscle force in the gastrocnemius (GC), vastus intermedius (VI), and soleus (SOL) muscles of rats. The muscle force was measured by attaching a hook to the tendon using a load cell, and the MMG was measured using a charged-coupled device-type displacement sensor at the middle of the target muscle. The MMG-twitch waveform was very similar to that of the muscle force; however, the half relaxation time and relaxation time (10%), which are relaxation parameters, were prolonged compared to those of the muscle force. The MMG amplitude correlated with the muscle force. Since stimulation frequencies that are necessary to evoke tetanic progression have a significant correlation with the twitch parameter, there is a close relationship between twitch and tetanus in the MMG signal. Therefore, we suggest that the MMG, which is electrically induced and detected by a laser displacement sensor, may be an alternative tool for measuring muscle strength.

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  • Plasma Arginase-1 Level Is Associated with the Mental Status of Outpatients with Chronic Liver Disease Reviewed International journal

    Noriyoshi Ogino, Fusao Ikeda, Shihoko Namba, Shinnosuke Ohkubo, Tomoaki Nishimura, Hiroyuki Okada, Satoshi Hirohata, Narufumi Suganuma, Keiki Ogino

    DIAGNOSTICS   11 ( 2 )   2021.2

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    While plasma arginase-1 has been suggested as a biomarker of mental status in healthy individuals, it has not been evaluated in patients with chronic liver disease. This cross-sectional study investigated the utility of plasma arginase-1 for screening mental status in patients with chronic liver disease. This study included outpatients with chronic liver disease who underwent regular check-ups at Okayama University Hospital between September 2018 and January 2019. In addition to the standard blood tests, the plasma arginase-1 level was analyzed. The patients' mental status was assessed using the Japanese version of the General Health Questionnaire-28 (GHQ-28). The associations between mental status and various parameters, including plasma arginase-1, were investigated using logistic regression analysis. Among 114 participating patients, 8 were excluded, comprising 6 with insufficient blood samples for plasma arginase-1 measurement and 2 with incomplete questionnaires. Multivariate binomial logistic regression analysis revealed that plasma arginase-1 was significantly and negatively associated with the GHQ-total score, especially somatic symptoms. Therefore, plasma arginase-1 may be a useful biomarker for assessing the mental status of outpatients with chronic liver disease.

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  • Bile acids aggravate nonalcoholic steatohepatitis and cardiovascular disease in SHRSP5/Dmcr rat model Reviewed International journal

    Shusei Yamamoto, Ikumi Sato, Natsuki Fukuhama, Natsumi Akiyama, Miku Sakai, Shota Kumazaki, Shang Ran, Satoshi Hirohata, Kazuya Kitamori, Yukio Yamori, Shogo Watanabe

    Experimental and Molecular Pathology   114   104437 - 104437   2020.6

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    BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is linked to an increased risk of cardiovascular disease, regardless of the risk factors in metabolic syndrome. However, the intermediary factors between NASH and cardiovascular disease are still unknown. A previous study revealed that serum and hepatic bile acid (BA) levels are increased in some NASH patients. We aimed to examine whether NASH and cardiovascular disease were aggravated by BA using an animal model. METHOD AND RESULTS: From 10 to 18 weeks of age, SHRSP5/Dmcr rats divided into 3 groups were fed 3 types of high-fat and high-cholesterol (HFC) diets which were changed in the cholic acid (CA) concentration (0%, 2%, or 4%). The nitro oxide synthase inhibition (L-NAME) was administered intraperitoneally from 16 to 18 weeks of age. The 4% CA groups showed the worst LV dysfunction and myocardial fibrosis, and demonstrated severe hepatic fibrosis and lipid depositions. In addition, a large amount of lipid accumulation was observed in the aortas of the 4% CA group, and NFκB and VCAM-1 gene expression levels were increased. These findings were not seen in the 0% CA group. CONCLUSION: In the SHRSP5/Dmcr rat model, NASH and cardiovascular disease were aggravated with increasing BAs concentrations in an HFC diet.

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  • Activated clotting time on the day of atrial fibrillation ablation for minimally interrupted and uninterrupted direct oral anticoagulation therapy: Sequential changes, differences among direct oral anticoagulants, and ablation safety outcomes Reviewed International journal

    Hirosuke Yamaji, Takashi Murakami, Kazuyoshi Hina, Shunich Higashiya, Hiroshi Kawamura, Masaaki Murakami, Shigeshi Kamikawa, Satoshi Hirohata, Shozo Kusachi

    JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY   30 ( 12 )   2823 - 2833   2019.12

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    Background Activated clotting time (ACT)-guided heparinization is used during atrial fibrillation (AF) ablation. Differences in sensitivity to ACT assays have been identified among different direct oral anticoagulants (DOACs). Objective We aimed to examine ACT just before ablation (pre-ACT) for different ablation start times (9:00, 11:00, 13:00, or 15:00) and ablation safety outcomes in minimally interrupted (min-Int) and uninterrupted (Unint) DOAC regimens and examine differences in pre-ACT values among four DOACs. Methods Consecutive patients were randomized into the min-Int (n = 307) or Unint (n = 277) groups. DOACs examined were apixaban, dabigatran, edoxaban, and rivaroxaban. Results No sequential changes in pre-ACT values were observed for each DOAC used and for all four DOACs combined in the min-Int and Unint groups. There was no meaningful difference in pre-ACT at each ablation start time between the groups. Clinically significant differences in overall pre-ACT were not obtained between the groups (138 +/- 24 vs 142 +/- 23 seconds). The pre-ACT (baseline) value for dabigatran was on average 29 seconds higher than that for the other three DOACs. The min-Int and Unint groups showed similar thromboembolic (0% vs 0%) and bleeding event rates (major, 1% vs 0%; all, 3.5% vs 2.5%). Conclusion The pre-ACT did not show a sequential change in the min-Int and Unint groups. No notable differences in the time-dependent change in pre-ACT between the groups were observed. Variations in baseline ACT suggest the need for moderate adjustment of ACT for adequate modification of heparin dose for the other three DOACs. Both regimens provided similar acceptable AF ablation safety outcomes.

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  • Effects of Oral Anticoagulants on Patients With Atrial Fibrillation Aged 90 Years and Older: Comparison Among Direct Oral Anticoagulant, Warfarin Anticoagulant, and Nonanticoagulation Reviewed International journal

    Hirosuke Yamaji, Shunichi Higashiya, Takashi Murakami, Kazuyoshi Hina, Hiroshi Kawamura, Masaaki Murakami, Shigeshi Kamikawa, Satoshi Hirohata, Shozo Kusachi

    JOURNAL OF CARDIOVASCULAR PHARMACOLOGY   74 ( 3 )   246 - 254   2019.9

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    This study aimed to investigate the effects of anticoagulants on ultra-aged patients with nonvalvular atrial fibrillation (AF). We retrospectively studied 320 consecutive patients with AF (median age, 91 years; range 90-100.1 years). Patients were categorized as follows: patients taking direct oral anticoagulant (DOAC group, n = 93), those taking warfarin (warfarin group, n = 147), and those not taking oral anticoagulants (non-OAC group, n = 80). During the follow-up periods (median 3.00 years; first and fourth quantiles, 1.13 and 4.56 years, respectively), in thromboembolic events, the DOAC, warfarin, and non-OAC groups showed the lowest (0%, 0/93; 0%/year), intermediate (4.7%, 7/149; 1.43%/year), and highest (5%, 4/80; 2.65%/year) incidence rates, respectively. In major bleeding events, the DOAC, warfarin, and non-OAC groups showed the highest (9.67%, 9/96; 5.00%/year), intermediate (8.1%, 12/149; 2.46%/year), and lowest (0%, 0/80; 0%/year) incidence rates, respectively. These differences in the relationships of the 3 groups were statistically significant. Confounding factors did not affect these results. Bruises associated with impairment of motor function with aging caused major bleeding in approximately 60% of major bleeding cases. The Cox proportional hazards model revealed that warfarin decreased mortality, whereas antiplatelet drugs increased mortality. In conclusion, DOACs had considerably high incidence of major bleeding events, whereas absence of OAC treatment was associated with substantially high thromboembolic events. Warfarin showed acceptable incidence ratios of both events. At present, warfarin is thus believed to be adequate for ultra-aged ($90 years) patients with nonvalvular AF. Avoidance of bruises was important to prevent major bleeding events. Antiplatelet drugs were suggested not to be adequate for these patients.

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  • 経皮的冠動脈インターベンション(PCI)支援ロボットの現状と将来展望

    松浦龍太郎, 渡邊彰吾, 廣畑 聡

    臨床画像   65 ( 4 )   480 - 485   2019.4

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  • Bile Acid Metabolism is an Intermediary Factor between Non-Alcoholic Steatohepatitis and Ischemic Heart Disease in SHRSP5/Dmcr Rats

    Shota Kumazaki, Mayu Nakamura, Shun Sasaki, Rina Tagashira, Nozomi Maruyama, Ikumi Sato, Shusei Yamamoto, Shang Ran, Shinichi Usui, Ryoko Shinohata, Takashi Ohtsuki, Satoshi Hirohata, Kazuya Kitamori, Mari Mori, Yukio Yamori, Shogo Watanabe

    Journal of Nutrition & Food Sciences   09 ( 04 )   2019

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  • Adjunctive left anterior line ablation induced left atrial dysfunction and dyssynchrony in atrial fibrillation ablation. Reviewed

    Yamaji H, Murakami T, Hina K, Higashiya S, Kawamura H, Murakami M, Kamikawa S, Hirohata S, Kusachi S

    Heart and vessels   34 ( 2 )   331 - 342   2018.8

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    We evaluated the effects of adjunctive left anterior line (LAL) ablation on LA dyssynchrony and function using real-time three-dimensional echocardiography (3DE) in connection with thromboembolic complications and tachyarrhythmia recurrence in patients with persistent atrial fibrillation (AF). We randomly and prospectively assigned consecutive persistent AF patients to the LAL (n=52, 65 +/- 7years) and control groups (n=50, 64 +/- 10years). In the LAL group, extensive encircling pulmonary vein isolation (EEPVI), roof line ablation, and LAL ablation regardless of the extent of the low-voltage area (LVA) were performed. The control group underwent EEPVI and roof line ablation. After ablation, 3DE demonstrated LA dyssynchrony in 23 (46%) and 4 patients (8%, P<0.001) of the LAL and control groups, respectively. Baseline LA LVAs were relatively small in most patients and there were no significant differences in extent of LVA between control and LAL groups or between patients with and without dyssynchrony. During the follow-up periods (771 +/- 121days), patients with LA dyssynchrony in the LAL group did not show significant differences in symptomatic thromboembolic events (0%) and atrial tachyarrhythmia recurrence (39%) from patients without LA dyssynchrony in the LAL (0% and 30%) and control groups (0% and 32%, respectively). LA ejection fraction and active emptying fraction were lower by 9% on average in the LAL group than in the control group (P<0.0001). Similarly, in the LAL group, LA ejection fraction, active emptying fraction, and expansion index were significantly lower by approximately 7%, 8%, and 15%, respectively, in LA with dyssynchrony than those in LA without dyssynchrony. In conclusion, LA dyssynchrony and LA hypofunction were induced by LAL ablation in patients with persistent AF and relatively mild LVA. LAL ablation with or without LA dyssynchrony is thought not to affect thromboembolic complications or atrial tachyarrhythmia recurrence.

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  • Circulating adipocyte fatty acid-binding protein is a predictor of cardiovascular events in patients with stable angina undergoing percutaneous coronary intervention International journal

    Wataru Takagi, Toru Miyoshi, Masayuki Doi, Keisuke Okawa, Kazumasa Nosaka, Tomoyuki Nishibe, Naoaki Matsuo, Satoshi Hirohata, Hiroshi Ito

    BMC CARDIOVASCULAR DISORDERS   17 ( 1 )   83 - 106   2017.10

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    Background: Adipocyte fatty acid-binding protein (A-FABP) is expressed in both adipocytes and macrophages. Recent studies have shown that A-FABP is secreted by adipocytes and that the A-FABP concentration is associated with obesity, insulin resistance, and atherosclerosis. We have reported that the coronary atherosclerotic burden is associated with the serum A-FABP concentration. In the present study, we investigated whether the serum A-FABP concentration is associated with prognosis in patients with stable angina pectoris who have undergone percutaneous coronary intervention (PCI).
    Methods: This was a prospective single-center trial. In total, 130 patients with stable angina pectoris undergoing their first PCI were enrolled from August 2008 to July 2010 at Kagawa Prefectural Central Hospital. The primary endpoints were cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, revascularization, and hospitalization for heart failure.
    Results: During the follow-up (median, 50 months; interquartile range, 23-66 months), 49 cardiovascular events occurred. Kaplan-Meier analysis showed that the cumulative incidence of the primary endpoints in the high AFABP group (median A-FABP concentration of &gt;= 18.6 ng/ml) was greater than that in the low A-FABP group. Cox analysis showed that the A-FABP concentration was an independent predictor of cardiovascular events adjusted for age and the presence of multi-vessel disease (hazard ratio, 1.03; 95% confidence interval, 1.01-1.04; p = 0.01).
    Conclusion: The serum A-FABP concentration is associated with prognosis in patients with stable angina undergoing PCI, suggesting that the serum A-FABP concentration could be useful for risk assessment of secondary prevention.

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  • EPA/AA CAN BE A PREDICTIVE FACTOR IN THE PATIENTS WITH CORONARY ARTERY DISEASE IN THE STRONG STATIN ERA

    Naoaki Matsuo, Atsushi Takaishi, Nobuhiko Oonishi, Yukari Nakano, Kenzou Kagawa, Tatsuya Yamaji, Yuuichi Katou, Kazuna Hayashi, Masayuki Ueeda, Satoshi Hirohata

    ATHEROSCLEROSIS   263   E196 - E197   2017.8

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  • Diverse Functions of a Disintegrin and Metalloproteinase with Thrombospondin Motif-1 Reviewed

    Satoshi Hirohata, Junko Inagaki, Takashi Ohtsuki

    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN   137 ( 7 )   811 - 814   2017.7

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    A disintegrin and metalloproteinase with thrombospondin motif-1 (ADAMTS1) was initially cloned from a colon cachexia cell line. In the last 20 years, novel matrix metalloproteinase (MMP) genes were found, and in addition to their original members (MMPs and membrane-type MMPs), the current MMP family contains a disintegrin and metalloproteinases (ADAMs) and ADAMTS. ADAM and ADAMTS play essential roles in organogenesis as well as various diseases including osteoarthritis. ADAMTS has 19 members and can be divided into several groups according to their substrates. ADAMTS1, the first member of ADAMTS identified, is located on chromosome 21 very close to another ADAMTS member, ADAMTS5. Interestingly, ADAMTS1 is not highly expressed in normal tissues. One stimulation such as inflammation quickly induces ADAMTS1 expression. We found that hypoxia induced ADAMTS1 expression in endothelial cells, and serum ADAMTS1 levels were elevated in acute myocardial infarction patients. Once the artery was reperfused, the serum ADAMTS1 level quickly returned to the normal level. We also found that ADAMTS1 has specific roles in angiogenesis and lymphangiogenesis, and these functions were not related to its protease activity. It is also interesting that ADAMTS1 is likely to have a unique role in the tumor microenvironment. We also analyzed ADAMTS1-deficient mice and the results suggested that ADAMTS1 has diverse biological functions.

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  • A rapid and precise method for measuring plasma apoE-rich HDL using polyethylene glycol and cation-exchange chromatography: a pilot study on the clinical significance of apoE-rich HDL measurements Reviewed International journal

    Toru Ikeda, Ryoko Shinohata, Masaaki Murakami, Kazuyoshi Hina, Shigeshi Kamikawa, Satoshi Hirohata, Shozo Kusachi, Arisa Tamura, Shinichi Usui

    CLINICA CHIMICA ACTA   465   112 - 118   2017.2

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    Background: High-density lipoprotein (HDL) containing apolipoprotein E (apoE-rich HDL) represents only a small portion of plasma HDL. Reliable methods for determining and isolating apoE-rich HDL have not been well studied.
    Methods: We established a novel analytical method for apoE-rich HDL using polyethylene glycol and a cation-exchange column (PEG-column method). Furthermore, we examined biochemical correlates of apoE-rich HDL-cholesterol (HDL-C) in 36 patients who underwent coronary computed tomographic angiography.
    Results: Our PEG-column method demonstrated high reproducibility (coefficient of variation &lt;3.52%) and linearity up to 15 mg/dl for apoE-rich HDL-C concentrations. Isolated apoE-rich HDL exhibited a larger diameter (14.8 nm) than apoE-poor HDL (10.8 nm) and contained both apoE and apoA-I. ApoE-rich HDL-C concentrations correlated significantly with triglycerides (r(s) = -0.646), LDL size (r(s) = 0.472), adiponectin (r(s) = 0.476), and other lipoprotein components. No significant correlation was obtained with the coronary calcium score. Multiple regression analysis revealed that plasma triglycerides and adiponectin concentrations remained significant independent predictors of apoE-rich (adjusted R-2 = 0.486) but not apoE-poor HDL-C.
    Conclusions: The PEG-column method demonstrated, to various degrees, significant correlations between HDL subtractions and several lipid-related biomarkers involved in an atherogenic lipoprotein profile. Our separation technique for apoE-rich HDL is useful to clarify the role of apoE-rich HDL in atherosclerosis. (C) 2016 Elsevier B.V. All rights reserved.

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  • Early initiation of eicosapentaenoic acid and statin treatment is associated with better clinical outcomes than statin alone in patients with acute coronary syndromes: 1-year outcomes of a randomized controlled study Reviewed International journal

    Kazumasa Nosaka, Toru Miyoshi, Mutsumi Iwamoto, Masahito Kajiya, Keisuke Okawa, Saori Tsukuda, Fumi Yokohama, Masahiro Sogo, Tomoyuki Nishibe, Naoaki Matsuo, Satoshi Hirohata, Hiroshi Ito, Masayuki Doi

    INTERNATIONAL JOURNAL OF CARDIOLOGY   228   173 - 179   2017.2

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    Background: Early initiation of EPA treatment in combination with a statin within 24 h after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (MI) reduces inflammation and ventricular arrhythmia compared with statin monotherapy; however, the impact of early initiation of EPA treatment on cardiovascular events is unclear. We determined whether early eicosapentaenoic acid (EPA) treatment in patients with acute coronary syndrome (ACS) reduces adverse cardiovascular events.
    Methods: This prospective, open-label, blind end point-randomized trial consisted of 241 patients with ACS. Patients were randomly assigned to receive pitavastatin (2mg/day) with or without 1800mg/day of EPA initiated within 24 h after PCI. The primary endpoint was defined as cardiovascular events occurring within 1 year, including death from a cardiovascular cause, nonfatal stroke, nonfatal MI and revascularization.
    Results: The mean EPA/ arachidonic acid ratio at follow-up was 0.40 in the control group and 1.15 in the EPA group. A primary endpoint event occurred in 11 patients (9.2%) in the EPA group and 24 patients (20.2%) in the control group (absolute risk reduction, 11.0%; hazard ratio, 0.42; 95% confidence interval, 0.21 to 0.87; P = 0.02). Notably, death from a cardiovascular cause at 1 year was significantly lower in the EPA group than in the control group (0.8% vs. 4.2%, P = 0.04).
    Conclusions: Early initiation of treatment with EPA combined with statin after successful primary PCI reduced cardiovascular events after ACS. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.

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  • Subclavian steal syndrome: A case report and review of advances in diagnostic and treatment approaches Reviewed

    Issei Komatsubara, Jun Kondo, Maki Akiyama, Hidemi Takeuchi, Kunio Nogami, Shinichi Usui, Satoshi Hirohata, Shozo Kusachi

    Cardiovascular Revascularization Medicine   17 ( 1 )   54 - 58   2016.1

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    Using recently developed diagnostic and treatment methods, we successfully diagnosed and treated a case of subclavian steal syndrome. Syncope and left upper arm weakness suggested ischemia of the cerebral and left upper arm circulation. Volume-plethysmographic blood pressure measurements clarified the differences between the upper arms simultaneously. A high-resolution Doppler instrument revealed a retrograde left vertebral artery waveform, indicating subclavian steal syndrome. Aortography demonstrated proximal left subclavian artery occlusion. The patient was treated with stent implantation via a femoral approach using the latest equipment. Advances in diagnostic and treatment approaches for this syndrome are reviewed in connection with this case.Summary: We present a case of subclavian steal syndrome successfully diagnosed using the latest technology and treated with stent implantation. The syndrome and its treatment are reviewed.

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  • Clinical Experience : Estimation of Vascular Conditions by Means of the Analysis of the Arterial Pressure Waveform Changes in Patients with Septic Shock

    39 ( 12 )   747 - 751   2015.12

  • Eosinophil Cationic Protein Shows Survival Effect on H9c2 Cardiac Myoblast Cells with Enhanced Phosphorylation of ERK and Akt/GSK-3 beta under Oxidative Stress

    Hiroko Ishii, Shigeshi Kamikawa, Satoshi Hirohata, Akifumi Mizutani, Koji Abe, Masaharu Seno, Toshitaka Ohashi, Yoshifumi Ninomiya

    ACTA MEDICA OKAYAMA   69 ( 3 )   145 - 153   2015.6

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    Eosinophil cationic protein (ECP) is well known as a cationic protein contained in the basic granules of activated eosinophils. Recent studies have reported that ECP exhibits novel activities on various types of cells, including rat neonatal cardiomyocytes. Here we evaluated the effects of ECP on rat cardiac myoblast H9c2 cells. Our results showed that ECP enhanced the survival of the cells, in part by promoting the ERK and Akt/GSK-3 beta signaling pathways. ECP attenuated the cytotoxic effects of H2O2 on H9c2 cells as well as the production of reactive oxygen species, the number of apoptotic cells and caspase 3/7 activity in the cells. In conclusion, ECP activated the ERR and Akt/GSK-3 beta pathways, resulting in anti-oxidative effects on H9c2 cells that attenuated apoptosis.

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  • Early eicosapentaenoic acid treatment after percutaneous coronary intervention reduces acute inflammatory responses and ventricular arrhythmias in patients with acute myocardial infarction: A randomized, controlled study Reviewed International journal

    Masayuki Doi, Kazumasa Nosaka, Toru Miyoshi, Mutsumi Iwamoto, Masahito Kajiya, Keisuke Okawa, Rie Nakayama, Wataru Takagi, Ko Takeda, Satoshi Hirohata, Hiroshi Ito

    INTERNATIONAL JOURNAL OF CARDIOLOGY   176 ( 3 )   577 - 582   2014.10

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    Objective: We examined whether early loading of eicosapenlaenoic acid (EPA) reduces clinical adverse events by 1 month, accompanied by a decrease in C-reactive protein (CRP) values in patients with acute myocardial infarction (MI).
    Background: Acute MI triggers an inflammatory reaction, which plays an important role in myocardial injury. EPA could attenuate the inflammatory response.
    Methods: This prospective, open-label, blinded endpoint, randomized trial consisted of 115 patients with acute MI. They were randomly assigned to the EPA group (57 patients) and the control group (58 patients). After percutaneous coronary intervention (PCI), 1800 mg/day of EPA was initiated within 24 h.The primary endpoint was composite events, including cardiac death, stroke, re-infarction, ventricular arrhythmias, and paroxysmal atrial fibrillation within 1 month.
    Results: Administration of EPA significantly reduced the primary endpoint within 1 month (10.5 vs 29.3%, p = 0.01), especially the incidence of ventricular arrhythmias (7.0 vs 20.6%, p = 0.03). Peak CRP values after PCI in the EPA group were significantly lower than those in the control group (median [interquartile range], 8.2 [5.6-10.21 mg/dl vs 9.7 [7.6-13.91 mg/dl p &lt; 0.01). Logistic regression analysis showed that EPA use was an independent factor related to ventricular arrhythmia until 1 month, with an odds ratio of 0.29 (95% confidence interval, 0.09 to 0.96, p = 0.04).
    Conclusions: Early EPA treatment after PCI in the acute stage of MI reduces the incidence of ventricular arrhythmias, and lowers CRP values. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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  • Low serum level of secreted frizzled-related protein 5, an anti-inflammatory adipokine, is associated with coronary artery disease Reviewed International journal

    Toru Miyoshi, Masayuki Doi, Shinichi Usui, Mutsumi Iwamoto, Masahito Kajiya, Ko Takeda, Kazumasa Nosaka, Rie Nakayama, Keisuke Okawa, Wataru Takagi, Kazufumi Nakamura, Satoshi Hirohata, Hiroshi Ito

    ATHEROSCLEROSIS   233 ( 2 )   454 - 459   2014.4

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    Objective: Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipokine that is associated with insulin resistance in animals. To extend these observations to humans, we investigated the association of serum SFRP5 levels in subjects with and without coronary artery disease (CAD).
    Methods: Subjects (n = 185, 68 + 11 years, 79% male) suspected of having CAD were enrolled in the study and were divided into two groups, CAD and non-CAD subjects, according to the results of their coronary angiographies. Serum SFRP5 levels of the subjects were measured by an enzyme-linked immunosorbent assay.
    Results: The serum SFRP5 levels in the subjects with CAD were significantly lower than those in the non-CAD subjects (median [interquartile range]: 47.7 [26.6] vs. 52.4 [29.6] ng/mL, respectively; p = 0.02). The serum SFRP5 levels significantly correlated with body mass index, the homeostasis model of assessment of insulin resistance, adiponectin levels, and CAD severity. Multivariate logistic regression analysis revealed that a decreased serum SFRP5 level (log transformed) was independently associated with CAD for all subjects (adjusted odds ratio, 0.36; 95% confidence interval, 0.14-0.94; p = 0.03).
    Conclusion: Serum SFRP5 levels are significantly associated with CAD in humans, suggesting that low SFRP5 levels may contribute to CAD. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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  • New Estimation Method of Total Creatine Phosphokinase Release in Early Stage in Acute Myocardial Infarction

    Kitawaki T, Oka H, Usui S, Hirohata S, Kusachi S

    International Journal of Cardiovascular and Cerebrovascular Disease   2 ( 2 )   18 - 27   2014

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  • Serum adipocyte fatty acid-binding protein is independently associated with complex coronary lesions in patients with stable coronary artery disease

    Masahito Kajiya, Toru Miyoshi, Masayuki Doi, Shinichi Usui, Mutsumi Iwamoto, Ko Takeda, Kazumasa Nosaka, Rie Nakayama, Satoshi Hirohata, Shozo Kusachi, Kazufumi Nakamura, Hiroshi Ito

    HEART AND VESSELS   28 ( 6 )   696 - 703   2013.11

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    The association between circulating adipocyte fatty acid-binding protein (A-FABP) levels and coronary artery disease (CAD) is reported. We assessed whether plasma A-FABP levels are associated with angiographic coronary lesion morphology in patients with stable CAD. Serum A-FABP levels were analyzed in 115 patients with stable CAD (mean age 69 +/- 10 years; 80 % men). These patients were angiographically studied and divided into two groups: simple lesions (n = 34) and complex lesions (n = 81). We also compared 50 age- and gender-matched controls with no evidence of CAD. Serum A-FABP levels in patients with stable CAD were significantly higher than those in controls. In patients with stable CAD, serum A-FABP levels were significantly higher in patients with complex lesions than in those with simple lesions: median (25th-75th percentile), 23.4 (17.7-30.8) vs 18.2 (12.2-24.7) ng/ml, P &lt; 0.01. Serum A-FABP levels were also significantly associated with angiographic scores of extent of coronary lesion (r = 0.21, P = 0.02). Multiple logistic analysis that included dyslipidemia, statin therapy, and extent score demonstrated that serum A-FABP was independently associated with complex lesions. The multiple adjusted odds ratio for a complex lesion with a serum A-FABP level (per doubling) was 2.38 (95 % confidence interval, 1.03-6.41; P = 0.03). High serum A-FABP levels were significantly associated with complex coronary lesions in patients with stable CAD, suggesting that high A-FABP levels may be involved in coronary plaque vulnerability.

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  • Adaptive-servo ventilation combined with deep sedation is an effective strategy during pulmonary vein isolation International journal

    Takashi Murakami, Hirosuke Yamaji, Kenji Numa, Hiroshi Kawamura, Masaaki Murakami, Shunichi Higashiya, Shigeshi Kamikawa, Kazuyoshi Hina, Satoshi Hirohata, Shozo Kusachi

    Europace   15 ( 7 )   951 - 956   2013.7

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    AimsPulmonary vein isolation (PVI) by catheter ablation for atrial fibrillation (AF) requires suppression of patient restlessness by sufficient sedation in addition to maintaining stable respiration. We applied adaptive-servo ventilation (ASV) and examined the effects of ASV combined with deep propofol sedation on PVI using a NavX.Methods and resultsWe analysed 75 paroxysmal AF (PAF) patients (62 ± 11 years
    53 men and 22 women) who underwent PVI for treatment of PAF using an ASV system combined with deep sedation (ASV group). Control patients included 75 consecutive PAF patients (62 ± 11 years
    51 men and 24 women) who underwent PVI just before introduction of the ASV system. Deep sedation was defined as a Ramsay sedation score of 6. The ASV group had a lower frequency of restless body movements compared with the control group during PVI (1.5 ± 0.7 vs. 7.8 ± 1.4 times, P &lt
    0.01). The frequency of respiratory compensation and EnGuide alignment of catheter position by the NavX was lower in the ASV (4.2 ± 3.3 and 8.8 ± 7.1 times) than control group (7.1 ± 5.1 and 15.2 ± 10.0 times, P &lt
    0.05 and &lt
    0.01, respectively). Consequently, significantly lower total electrical energy supply (48.7 ± 6.0 KJ) was required in the ASV than control group (64.5 ± 24.9 KJ, P &lt
    0.01). Further, significantly shorter fluoroscopy and procedural times were observed in the ASV (28 ± 5 and 109 ± 25 min) than the control group (33 ± 6 and 141 ± 38 min, respectively, P &lt
    0.01) and the AF recurrence rate was significantly lower in the ASV than the control group (12 vs. 25%, P &lt
    0.01).ConclusionASV combined with deep sedation is an effective strategy during PVI using the NavX in patients with PAF. © 2013 The Author.

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  • A potential association between the number of CA repeats in the promoter region of the ADAMTS9 gene with lymphatic metastasis of breast cancer

    Mikdat Bozer, Fatma Asik, Muradiye Acar, Hacer Haltas, Sibel Yenidunya, Metin Canbal, Vehap Topcu, Muhammet Ramazan Yigitoglu, Mehmet Gunduz, Esra Gunduz, Satoshi Hirohata, Kadir Demircan

    TURKISH JOURNAL OF MEDICAL SCIENCES   43 ( 5 )   671 - 677   2013

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    Aim: We investigated the effect of the number of cytosine-adenine (CA) repeats in the ADAMTS9 promoter region on breast cancer lymphatic metastasis.Materials and methods: Thirty-one postoperative breast cancer patients were selected and examined retrospectively. The patients were classified into 2 groups: metastatic or nonmetastatic. Thirty healthy women were selected as the control group, and their peripheral blood was obtained. Following DNA isolation from the cancer tissue specimens and peripheral blood, the promoter region of the ADAMTS9 gene was directly sequenced and the number of CA repeats was determined.Results: The number of CA repeats ranged between 19 and 21 in the control and metastatic groups. However, in the nonmetastatic group, the number of CA repeats ranged between 17 and 18. This difference in the median number of CA repeats between the control group and the nonmetastatic group was statistically significant.Conclusion: A potential relationship may exist between lymphatic metastasis in breast cancer and the number of CA repeats in the promoter region of the ADAMTS9 gene. Our study indicates a potential association between the number of CA microsatellite repeats in the promoter region of the ADAMTS9 gene and breast cancer lymphatic metastasis.

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  • ADAMTSの機能

    廣畑 聡

    血管新生研究の最先端   208 - 216   2013

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  • Usefulness of Dabigatran Etexilate as Periprocedural Anticoagulation Therapy for Atrial Fibrillation Ablation International journal

    Hirosuke Yamaji, Takashi Murakami, Kazuyoshi Hina, Shunichi Higashiya, Hiroshi Kawamura, Masaaki Murakami, Shigeshi Kamikawa, Satoshi Hirohata, Shozo Kusachi

    CLINICAL DRUG INVESTIGATION   33 ( 6 )   409 - 418   2013

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    The usefulness of dabigatran etexilate for the prevention of stroke in patients with atrial fibrillation (AF) has been reported.
    In this study the efficacy and safety of dabigatran etexilate for anticoagulation for AF ablation were examined.
    Patients were divided into three groups: Group 1, interrupted warfarin bridged by heparin between pre- and post-ablation; Group 2, continuous warfarin therapy; and Group 3, dabigatran etexilate therapy. Anticoagulation therapy with warfarin or dabigatran etexilate was performed from 30 days before to at least 90 days after AF ablation. Dabigatran etexilate was administered at 110 or 150 mg twice daily, depending on renal function and age.
    Patients' clinical characteristics, associated disorders, echocardiographic parameters and arrhythmia status were not different among the three groups. Procedural parameters such as procedural time and radiofrequency energy supply were also not different among the three groups. The dabigatran etexilate group and the warfarin groups had no embolic complications (stroke, cerebral transient ischaemic attack, deep venous thrombosis or pulmonary embolism). No pericardial tamponade was observed in the dabigatran etexilate group, while two patients in each of Group 1 (2/194, 1.0 %) and Group 2 (2/203, 0.98 %) developed cardiac tamponade, though the differences were not significant. Pericardial effusion and groin haematoma were observed in one patient each (1/105, 0.9 %) in the dabigatran etexilate group, and the incidences were not different from the warfarin group (Group 1: 4/194, 2.1 % and 2/194, 1.0 %; Group 2: 3/203, 1.5 % and 2/203, 1.0 %, respectively). As a whole, the safety outcomes did not differ among the three groups.
    Dabigatran etexilate is an effective and safe anticoagulation therapy for AF ablation. Thus, dabigatran etexilate appears to be useful as an alternative anticoagulant therapy to warfarin for AF ablation.

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  • Reduced Diurnal Variation of Heart Rate is Associated With Increased Plasma B-Type Natriuretic Peptide Level in Patients With Atrial Fibrillation International journal

    Shigeshi Kamikawa, Toru Miyoshi, Masayuki Doi, Naoko Orita, Mutsuko Sangawa, Takaaki Nakatsu, Youko Noguchi, Satoshi Hirohata, Shozo Kusachi, Kazufumi Nakamura, Hiroshi Ito

    CLINICAL CARDIOLOGY   36 ( 7 )   394 - 400   2013

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    BackgroundThe plasma B-type natriuretic peptide (BNP) level has been shown to be increased in patients with chronic atrial fibrillation (AF) independent of left ventricular ejection fraction (LVEF). The purpose of this study is to evaluate the relationship between the plasma BNP level and heart rate variation in patients with AF.HypothesisThe plasma BNP level is associated with heart rate variation in patients with AF.MethodsA total of 102 patients with AF and preserved LVEF were included from 2 hospitals. The ambulatory electrocardiographic recording and measurement of plasma BNP levels were performed simultaneously. Echo-Doppler parameters were measured as the average of 10 consecutive cardiac cycles.ResultsA difference in the mean heart rate between night and day (DIFF) and the standard deviation of the 5-miniute mean R-R interval (SDARR) were significantly associated with log-transformed BNP levels (r = -0.411, P < 0.001 and r = -0.243, P = 0.049, respectively). In echocardiography, the ratio of E velocity to early diastolic velocity, which reflects left ventricular (LV) filling pressure, was significantly correlated with the DIFF and SDARR, along with the log-transformed BNP level. Stepwise multiple linear regression analysis revealed that the DIFF and age were independent factors related with the BNP level (P < 0.01).ConclusionsThe reduced diurnal variation of heart rate was significantly associated with increased BNP, which is linked to LV diastolic dysfunction in patients with AF.

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  • Cyclic tensile strain inhibits interleukin-1 beta and tumor ncerosis factor-alpha-induced aggrecanase in human chondrosarcoma cell line OUMS-27 by stretch-activated channles

    Takashi Ohtsuki, Keiichiro Nishida, Satoshi Hirohata, Yoshifumi Ninomiya

    GLYCOBIOLOGY   22 ( 11 )   1582 - 1583   2012.11

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  • The tumor growth inhibitory effect of ADAMTS1 is accompanied by the inhibition of tumor angiogenesis

    Satoshi Hirohata, Takashi Ohtsuki, Masanari Obika, Hiroko Ogawa, Shozo Kusachi, Yoshifumi Ninomiya

    GLYCOBIOLOGY   22 ( 11 )   1559 - 1559   2012.11

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  • Impact of MDA-LDL/LDL-C and AA/EPA ratio to plaque vulnerability in patients with stable angina pectoris

    Hiroaki Otsuka, Masayuki Ueeda, Takuro Masuda, Yasunori Arai, Daisuke Yamada, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Shozo Kusachi, Hiroshi Ito

    CIRCULATION   125 ( 19 )   E697 - E697   2012.5

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  • Elevated serum adipocyte fatty acid-binding protein concentrations are independently associated with renal dysfunction in patients with stable angina pectoris International journal

    Mutsumi Iwamoto, Toru Miyoshi, Masayuki Doi, Ko Takeda, Masahito Kajiya, Kazumasa Nosaka, Rie Nakayama, Satoshi Hirohata, Shinichi Usui, Shozo Kusachi, Kosuke Sakane, Kazuhfumi Nakamura, Hiroshi Ito

    CARDIOVASCULAR DIABETOLOGY   11 ( 26 )   26 - 26   2012.3

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    Background: Chronic kidney disease (CKD) is associated with cardiovascular events. Adipocyte fatty acid-binding protein (A-FABP) plays an important role in atherosclerosis. We investigated whether plasma A-FABP is involved in renal function in patients with stable angina pectoris.
    Methods: A total of 221 patients with significant coronary artery stenosis were enrolled after coronary angiography. CKD was defined as an estimated glomerular filtration rate (eGFR) &lt; 60 ml/min/1.73 m(2). The severity of coronary stenosis was assessed using a modified Gensini score and coronary angiography. Serum A-FABP levels were determined by enzyme-linked immunosorbent assay.
    Results: Serum A-FABP levels were significantly correlated with both eGFR (r = -0.41, p &lt; 0.01) and the severity of coronary artery stenosis (r = 0.16, p = 0.02), and these relationships remained significant after adjusting for confounding factors. The prevalence of CKD and multi-vessel disease was significantly higher among patients with serum A-FABP levels above the median value of 20.3 ng/ml than among patients with serum A-FABP levels below the median value (57% vs. 27%, p &lt; 0.01 and 64% vs. 48%, p = 0.02, respectively). Multivariate analysis revealed that the presence of three-vessel disease in comparison with single-vessel disease was independently associated with the higher A-FABP (per doubling) (odds ratio; 2.26, 95% confidential interval; 1.28-3.98, p &lt; 0.01) and tended to be associated with the lower eGFR (p = 0.06).
    Conclusion: Serum A-FABP may have a significant role in the interplay between renal dysfunction and coronary atherosclerosis.

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  • Sufficient pulmonary vein image quality of non-enhanced multi-detector row computed tomography for pulmonary vein isolation by catheter ablation International journal

    Hirosuke Yamaji, Kazuyoshi Hina, Hiroshi Kawamura, Takashi Murakami, Masaaki Murakami, Satoshi Hirohata, Natsuki Ohmaru, Shozo Kusachi

    EUROPACE   14 ( 1 )   52 - 59   2012.1

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    Aims We evaluated the quality of non-enhanced multi-detector row computed tomography (MDCT) images of the pulmonary vein (PV) and the clinical results of catheter ablation to isolate the PV for treatment of atrial fibrillation (AF) without the use of contrast medium in patients with chronic kidney disease (CKD).
    Methods and results We compared PV images quantitatively and qualitatively between non-enhanced and enhanced images (n = 50). Procedural parameters and clinical outcomes were compared between catheter ablation for AF referring solely to non-enhanced MDCT in CKD patients (n = 20) and using enhanced MDCT images integrated with electroanatomic mapping in non-CKD patients (n = 30). In gross anatomy, complete agreement was obtained between non-enhanced and enhanced MDCT images. Bland-Altman plots and cumulative coefficient variation showed good agreement in PV diameter determination between non-enhanced and enhanced MDCT images. There were no statistically significant differences in procedural or fluoroscopic times between PV isolation only referring to non-enhanced MDCT images and that using enhanced MDCT images integrated with electroanatomic mapping. Similarly, the ablation success rate and AF-free status at 3 months after PV isolation did not differ between PV isolation referring only to non-enhanced MDCT images and that using an electroanatomic integration system. No complications occurred in PV isolation with or without enhanced MDCT.
    Conclusions Non-enhanced MDCT provides adequate PV image quality both quantitatively and qualitatively. The present study suggests that catheter ablation referring solely to non-enhanced MDCT images for AF could be performed with clinically acceptable results. These findings warrant further studies involving a much larger number of patients to confirm the present results.

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  • Serum hepatitis B virus DNA before liver transplantation correlates with HBV reinfection rate even under successful low-dose hepatitis B immunoglobulin prophylaxis Reviewed International journal

    Tetsuya Yasunaka, Akinobu Takaki, Takahito Yagi, Yoshiaki Iwasaki, Hiroshi Sadamori, Kazuko Koike, Satoshi Hirohata, Masashi Tatsukawa, Daisuke Kawai, Hidenori Shiraha, Yasuhiro Miyake, Fusao Ikeda, Haruhiko Kobashi, Hiroaki Matsuda, Susumu Shinoura, Ryuichi Yoshida, Daisuke Satoh, Masashi Utsumi, Teppei Onishi, Kazuhide Yamamoto

    HEPATOLOGY INTERNATIONAL   5 ( 4 )   918 - 926   2011.12

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    Purpose The combination of hepatitis B immunoglobulin (HBIg) and nucleos(t)ide analogues has been accepted as the best treatment to control hepatitis B recurrence after orthotopic liver transplantation (OLT). However, the optimal dose of HBIg remains unclear. We have previously reported that high-dose HBIg in the early period followed by low-dose HBIg with nucleos(t)ide analogues offers reliable and cost-effective control of hepatitis B recurrence. The aim of this study was to investigate intrahepatic hepatitis B virus (HBV) reinfection status with our clinically successful protocol.
    Methods We quantified levels of intrahepatic HBV covalently closed circular (ccc) deoxyribonucleic acid (DNA) and serum hepatitis B core-related antigen (HBcrAg), a new serological marker that can estimate intrahepatic cccDNA levels. Nucleos(t)ide analogues were administered in all cases.
    Results No patients showed recurrence of hepatitis B surface antigen (HBsAg) or HBV-DNA. However, HBV, cccDNA, and HBcrAg were positive in 57% and 48% of patients after OLT, respectively. Pre-OLT serum HBV-DNA and HBcrAg levels correlated linearly with post-OLT cccDNA levels (r = 0.534, P &lt; 0.05, and r = 0.634, P &lt; 0.05, respectively). High serum HBV-DNA and HBcrAg levels, particularly with &gt; 3 log(10) copies/mL and &gt; 4 log(10) IU/mL, respectively, at the time of OLT, were associated with high levels of post-OLT cccDNA. Even with our successful protocol, nearly half of patients showed HBV reinfection.
    Conclusions Patients with high serum HBV-DNA and HBcrAg levels before OLT (particularly &gt; 3 log(10) copies/mL and &gt; 4 log(10) IU/mL, respectively) should be followed with care for HBV recurrence.

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  • Residual Diastolic Cross-Bridge and Decreased Expression of Energy Metabolism Genes in Hypertrophied Rat Hearts Induced by Chronic beta-Adrenergic Stimulation

    Kazufumi Nakamura, Daiji Miura, Juichiro Shimizu, Toru Miyoshi, Hiroko Toyota, Hiroshi Okuyama, Wakako Yoshikawa, Satoshi Akagi, Kunihisa Kohno, Masahi Yoshida, Hiroshi Morita, Satoshi Hirohata, Kengo Kusano, Tatsuhito Matsuo, Naoto Yagi, Hirhoshi Ito

    CIRCULATION   124 ( 21 )   2011.11

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  • ADAMTS1 Play Roles In Endothelial Cell Apoptosis

    Satoshi Hirohata, Masanari Obika, Faruk Hatipoglu, Kunihiko Hatanaka, Toru Miyoshi, Hiroko Ogawa, Kaori Sakamoto, Mehmet Z. Cilek, Junko Inagaki, Hiroshi Ito, Shozo Kusachi, Yoshifumi Ninomiya

    CIRCULATION   124 ( 21 )   2011.11

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  • 虚血性心疾患患者によるCAVIと冠動脈動脈硬化、左心機能の関連性の検討

    小川 弘子, 三好 亨, 土井 正行, 廣畑 聡, 草地 省蔵, 小出 典男

    臨床病理   59 ( 補冊 )   220 - 220   2011.10

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  • 発作性心房細動の出現率に対するarterial stiffness増加の影響

    小川 弘子, 三好 亨, 土井 正行, 廣畑 聡, 草地 省蔵, 小出 典男

    臨床病理   59 ( 補冊 )   220 - 220   2011.10

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  • ARB内服中高血圧患者に対するカルシウム拮抗薬もしくは利尿剤の追加がAugmentation indexへ与える影響

    三好 亨, 土井 正行, 小川 弘子, 廣畑 聡, 草地 省蔵, 小出 典男, 伊藤 浩

    臨床病理   59 ( 補冊 )   219 - 219   2011.10

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  • 急性冠症候群患者における血清ADAMTS1レベルの上昇

    廣畑 聡, 小比賀 真就, 幡中 邦彦, 小川 弘子, 三好 亨, 石井 裕子, 坂本 かおり, 草地 省蔵, 伊藤 浩, 二宮 善文

    臨床病理   59 ( 補冊 )   116 - 116   2011.10

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  • 非糖性糖尿病性未治療高血圧患者におけるUACRの分布とhigh-normalの頻度

    小川 弘子, 大丸 奈月, 中津 高明, 泉 礼司, 間島 圭一, 土岐 美沙子, 小林 亜紗子, 廣畑 聡, 池田 敏, 草地 省蔵

    臨床病理   59 ( 補冊 )   115 - 115   2011.10

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  • Olmesartan reduces arterial stiffness and serum adipocyte fatty acid-binding protein in hypertensive patients

    Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Shigeshi Kamikawa, Shinichi Usui, Hiroko Ogawa, Kosuke Sakane, Reishi Izumi, Yoshifumi Ninomiya, Shozo Kusachi

    HEART AND VESSELS   26 ( 4 )   408 - 413   2011.7

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    Adipocyte fatty acid binding protein (A-FABP) has been reported to be involved in insulin resistance, lipid metabolism, and atherosclerosis; however, little is known about the effect of medication on the change in circulating A-FABP in human subjects. We evaluated the effects of angiotensin II type 1 receptor blocker (ARB) on arterial stiffness and its association with serum A-FABP in patients with hypertension. Thirty patients newly diagnosed with essential hypertension were treated with olmesartan (20 mg/day), an ARB, for 6 months. Serum levels of A-FABP and high-sensitivity C-reactive protein (hsCRP) were examined and the cardio-ankle vascular index (CAVI), which is a marker of arterial stiffness, was also determined. Serum A-FABP at baseline was significantly correlated with the body mass index (r = 0.45, P = 0.01), homeostasis model assessment as a marker of insulin resistance (r = 0.53, P &lt; 0.01), and systolic blood pressure (r = 0.37, P = 0.047), and tended to be correlated with low-density lipoprotein cholesterol, triglyceride, and CAVI. Olmesartan treatment resulted in a significant decrease in CAVI, serum A-FABP levels, and hsCRP, besides a significant reduction of blood pressure. Multiple regression analysis revealed that the change in CAVI was independently correlated with the change in serum A-FABP. Olmesartan ameliorated arterial stiffness in patients with hypertension, which may be involved in the reduction of serum A-FABP.

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  • アンジオテンシンII受容体拮抗薬(オルメサルタン)によるサイトカイン発現抑制効果と心機能保持効果

    大月 孝志, 篠畑 綾子, 廣畑 聡, 草地 省蔵, 二宮 善文

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   43回・58回   126 - 126   2011.5

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  • IMPACT OF INCREASED ARTERIAL STIFFNESS AND WAVE REFLECTION ON THE PREVALENCE OF PAROXYSMAL ATRIAL FIBRILLATION

    Toru Miyoshi, Msayuki Doi, Satoshi Hirohata, Shozo Kusachi, Kazufumi Nakamura, Satoshi Nagase, Kunihisa Kono, Hiroshi Morita, Kengo Kusano, Hiroshi Ito

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   57 ( 14 )   E563 - E563   2011.4

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  • ANTI-INFLAMMATORY EFFECT OF OLMESARTAN ON CORONARY PLAQUE PROGRESSION, FINDING FROM THE IMPACT OF OLMESARTAN ON PROGRESSION OF CORONARY ATHEROSCLEROSIS: EVALUATION BY INTRAVASCULAR ULTRASOUND (OLIVUS) TRIAL

    Toru Miyoshi, Atsushi Hirohata, Shozo Kusachi, Satoshi Hirohata, Kazufumi Nakamura, Hiroshi Morita, Kengo Kusano, Hiroshi Ito

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   57 ( 14 )   E604 - E604   2011.4

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  • Association of serum levels of arachidonic acid and eicosapentaenoic acid with prevalence of major adverse cardiac events after acute myocardial infarction

    Masayuki Ueeda, Takenori Doumei, Yoichi Takaya, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Toru Miyoshi, Ryoko Shinohata, Shinichi Usui, Shozo Kusachi

    HEART AND VESSELS   26 ( 2 )   145 - 152   2011.3

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    We studied the association of serum levels of arachidonic acid (AA) and eicosapentaenoic acid (EPA) with the prevalence of major adverse cardiac events (MACE) after acute myocardial infarction (AMI). We measured serum AA and EPA on admission in 146 consecutive AMI patients. The primary clinical endpoint was occurrence of MACE, defined as cardiac death, occurrence of heart failure, reinfarction, recurrent angina pectoris, and requirement of coronary intervention. Common logarithmic transformed serum levels of AA (logAA) and EPA (logEPA) were used in the analyses. The optimum cutoff point of each fatty acid used to distribute patients into two groups for Kaplan-Meier analysis was determined by receiver operating characteristic curves analysis. MACE occurred in 40 patients (27.4%). Kaplan-Meier analysis disclosed that the group with a logAA above the cutoff point [145.3 mu g/mL (logAA 2.162)] showed a higher prevalence of MACE than those with a logAA below the cutoff point (P &lt; 0.01). Conversely, the prevalence of MACE was significantly higher in the group with a logEPA below the cutoff point [52.3 mu g/mL (logEPA 1.719)] compared to the group with a logEPA above it (P &lt; 0.01). Similar to logAA, logAA/logEPA showed significant differences in the MACE-free curve between the two groups (cutoff 1.301, P &lt; 0.001). Cox proportional hazards regression analysis suggested that logAA, logEPA, and logAA/logEPA were independently associated with the prevalence of MACE. Although the present study included a limited number of patients with single-time point measurement, the results suggested an association of logAA, logEPA, and logAA/logEPA with the prevalence of MACE after AMI. The present study warrants further studies involving a large number of patients to confirm that the serum levels of these fatty acids and their ratios are predictors of MACE after AMI.

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  • Distribution Pattern of Urine Albumin Creatinine Ratio and the Prevalence of High-Normal Levels in Untreated Asymptomatic Non-Diabetic Hypertensive Patients

    Natsuki Ohmaru, Takaaki Nakatsu, Reishi Izumi, Keiichi Mashima, Misako Toki, Asako Kobayashi, Hiroko Ogawa, Satoshi Hirohata, Satoru Ikeda, Shozo Kusachi

    INTERNAL MEDICINE   50 ( 16 )   1621 - 1629   2011

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    Background Even high-normal albuminuria is reportedly associated with cardiovascular events.
    Objective We determined the urine albumin creatinine ratio (UACR) in spot urine samples and analyzed the UACR distribution and the prevalence of high-normal levels.
    Patients and Methods The UACR was determined using immunoturbidimetry in 332 untreated asymptomatic non-diabetic Japanese patients with hypertension and in 69 control subjects. The microalbuminuria and macroalbuminuria levels were defined as a UCAR &gt;= 30 and &lt;300 mu g/mg.creatinine and a UCAR &gt;= 300 mu g/mg.creatinine, respectively.
    Results The distribution patterns showed a highly skewed distribution for the lower levels, and a common logarithmic transformation produced a close fit to a Gaussian distribution with median, 25th and 75th percentile values of 22.6, 13.5 and 48.2 mu g/mg.creatinine, respectively. When a high-normal UACR was set at &gt;20 to &lt;30 mu g/mg.creatinine, 19.9% (66/332) of the hypertensive patients exhibited a high-normal UACR. Micro-albuminuria and macroalbuminuria were observed in 36.1% (120/336) and 2.1% (7/332) of the patients, respectively. UACR was significantly correlated with the systolic and diastolic blood pressures and the pulse pressure. A stepwise multivariate analysis revealed that these pressures as well as age were independent factors that increased UACR.
    Conclusion The UACR distribution exhibited a highly skewed pattern, with approximately 60% of untreated, non-diabetic hypertensive patients exhibiting a high-normal or larger UACR. Both hypertension and age are independent risk factors that increase the UACR. The present study indicated that a considerable percentage of patients require anti-hypertensive drugs with antiproteinuric effects at the start of treatment.

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  • Significant relationship between changes in brachial-ankle pulse wave velocity relative to blood pressure elevation and coronary artery disease Reviewed International journal

    Issei Komatsubara, Shinichi Inoue, Rie Koumoto, Shigeru Matano, Tomoki Kitawaki, Satoshi Hirohata, Toru Miyoshi, Hiroko Ogawa, Ryoko Shinohata, Shozo Kusachi

    CORONARY ARTERY DISEASE   21 ( 7 )   407 - 413   2010.11

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    Objectives Based on well-established physiological theories, we studied correlations between changes in brachial-ankle pulse wave velocity (baPWV) relative to blood pressure (BP) elevation (elasticity of large-to-medium-sized arteries), and coronary artery disease (CAD).
    Methods The baPWV (in centimeters/second) and BP (in millimeters of mercury) were determined in 101 patients before, during, and/or after a cold pressor test using a volume-plethysmographic system.
    Results Significantly higher rates of increase in PWV relative to changes in BP were observed in the CAD(+) group than in the CAD(-) group when mean BP [median (25th-75th percentiles): 14.8 (8.3-24.9) vs. 8.6 (5.7-11.4) cm/s/mmHg, P &lt; 0.0001], and systolic [10.1 (6.0-17.5) vs. 6.4 (4.4-10.6) cm/s/mmHg, P = 0.0023] and diastolic BP [21.0 (14.0-34.4) vs. 10.8 (6.8-16.1) cm/s/mmHg, P &lt; 0.0001] were used as BP indices. Similarly, the rates of increase in baPWV showed a significant correlation with the extent of CAD. The rate of increase in baPWV obtained using the mean, systolic and diastolic BP as indices showed an area under the receiver operating characteristic curve of 0.68-0.76, sensitivity of 65-75%, and specificity of 65-75% for the detection of CAD. The area under the receiver operating characteristic curve, sensitivity, and specificity for the rate of increase were slightly higher than those for baseline baPWV and baseline baPWV/baseline BP ratio, but not to a significant degree.
    Conclusion The rate of increase in baPWV relative to BP elevation determined by cold pressor test is significantly and moderately correlated with CAD. To identify patients with CAD, the rate of increase in baPWV relative to changes in BP can provide considerable, but limited, information. Coron Artery Dis 21: 407-413 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

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  • Serum Adipocyte Fatty Acid-Binding Protein is Associated With Coronary Lesion Complexity in Patients With Coronary Artery Disease

    Masayuki Doi, Toru Miyoshi, Mutsumi Iwamoto, Kunio Nogami, Kajiya Masashi, Ko Takeda, Satoshi Hirohata, Shozo Kusachi, Hiroshi Ito

    CIRCULATION   122 ( 21 )   2010.11

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  • Chronic Kidney Disease is a Strong Predictor Related to the Severity of Coronary Artery Lesion in Patients with Stable Angina Pectoris

    Kazuhiro Dan, Masayuki Ueeda, Hiroaki Ohtsuka, Satoko Ugawa, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Shozo Kusachi, Kengo Kusano, Hiroshi Ito

    CIRCULATION   122 ( 2 )   E363 - E364   2010.7

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  • Combination Therapy of Calcium Channel Blocker and Angiotensin II Receptor Blocker Reduces Augmentation Index in Hypertensive Patients Reviewed International journal

    Masayuki Doi, Toru Miyoshi, Satoshi Hirohata, Shigeshi Kamikawa, Shinichi Usui, Youko Kaji, Kosuke Sakane, Hiroko Ogawa, Yoshifumi Ninomiya, Shozo Kusachi

    AMERICAN JOURNAL OF THE MEDICAL SCIENCES   339 ( 5 )   433 - 439   2010.5

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    Introduction: The optimal combination treatment for hypertension has not been established. We investigated the effect of a calcium channel blocker or a diuretic added to angiotensin II receptor blockers (ARBs) on the augmentation index (AI), as a marker of arterial stiffness and wave reflection, in hypertensive patients. Methods: Thirty-seven patients treated with ARBs were randomly allocated to either of the 2 groups receiving an ARB plus azelnidipine (AZ group) or trichlormethiazide (TCM group). Changes in brachial blood pressure (BP), AI, high-sensitive C-reactive protein (hsCRP), and serum asymmetric dimethylarginine, as an endogenous nitric oxide synthase inhibitor, were determined. Results: Systolic and diastolic blood pressure after 6 months were significantly reduced in both the groups similarly; however, after adjustment for baseline covariates, the extent of the reduction in AI (%) in the AZ group was significantly greater than in the TCM group (between-group difference was 3.2; 95% CI: 0.2-6.3; P = 0.03). The reduction of high-sensitive C-reactive protein (mg/L) and serum asymmetric dimethylarginine (mu mol/L) was significantly greater in the AZ group than in the TCM group (between-group difference was 0.18 and 0.05; 95% CI: -0.01 to 0.36 and -0.01 to 0.11; P = 0.04 and 0.02, respectively). Further, when patients were analyzed according to age younger than 60 years or older than 60 years, the reduction in AI in the AZ group aged older than 60 years was significantly greater than in the TCM group. Conclusion: The results suggest that azelnidipine has a more beneficial effect on vascular properties in combination therapy with ARB than trichlormethiazide.

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  • AHR (Acute hypoxia responsive element) As a New Tool Detecting Acute Hypoxia

    Mehmet Zeynel Cilek, Satoshi Hirohata, Omer Faruk Hatipoglu, Yoshifumi Ninomiya

    FASEB JOURNAL   24   2010.4

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  • Cardio-Ankle Vascular Index is Independently Associated with the Severity of Coronary Atherosclerosis and Left Ventricular Function in Patients with Ischemic Heart Disease Reviewed

    Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Kosuke Sakane, Shigeshi Kamikawa, Tomoki Kitawaki, Youko Kaji, Kengo Fukushima Kusano, Yoshifumi Ninomiya, Shozo Kusachi

    JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS   17 ( 3 )   249 - 258   2010

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    Aim: The cardio-ankle vascular index (CAVI) has been proposed as a new noninvasive marker of arterial stiffness independent of blood pressure. We investigated the association of the CAVI with coronary atherosclerosis and left ventricular (LV) systolic and diastolic function in patients with ischemic heart disease (IHD).
    Methods: A total of 206 consecutive subjects undergoing coronary angiography were enrolled. CAVI measurement and echocardiography were performed simultaneously. Patients having significant coronary stenosis were classified into the IHD group.
    Results: CAVI in the IHD group (n = 133) was significantly higher than in the non-IHD group (n = 73) (9.1 +/- 1.3 vs. 8.7 +/- 1.2, p = 0.02). In all IHD patients, CAVI was negatively correlated with LV ejection fraction (LVEF) (r = -0.31, p &lt; 0.01), LV mass index (r = 0.24, p &lt; 0.01) and angiographic scores of coronary atherosclerosis. Stepwise regression analysis revealed that CAVI was independently associated with LVEF, along with a history of myocardial infarction, LV mass index, and left atrial diameter in all IHD patients (p &lt; 0.01). In the sub-analysis of IHD patients with preserved LVEF, CAVI was correlated with echocardiographic parameters regarding LV diastolic function. Multivariate analysis demonstrated that the increased CAVI was significantly associated with LV diastolic dysfunction in patients with preserved LVEF.
    Conclusion: CAVI, a new parameter of aortic stiffness, was independently associated with LV systolic and diastolic function as well as coronary artery disease in IHD patients.

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  • Effect of Cilnidipine on Normal to Marginally Elevated Urine Albumin-Creatinine Ratio in Asymptomatic Non-Diabetic Hypertensive Patients An Exponential Decay Curve Analysis Reviewed International journal

    Takaaki Nakatsu, Shinji Toyonaga, Keiichi Mashima, Yoko Yuki, Aya Nishitani, Hiroko Ogawa, Toru Miyoshi, Satoshi Hirohata, Reishi Izumi, Shozo Kusachi

    CLINICAL DRUG INVESTIGATION   30 ( 10 )   699 - 706   2010

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    Background: High-normal urinary albumin excretion has been reported to have clinical significance with respect to progression of proteinuria and hypertension.
    Objective: We analysed the effect of cilnidipine (10 mg/day) on morning systolic blood pressure (SBP) and urine albumin-creatinine ratio (UACR) in 16 non-diabetic hypertensive patients with a normal to marginally elevated UACR (mean +/- SD 29.4 +/- 21.7; range 7.5-72.9 mg/g creatinine).
    Methods: Sequential home BP and UACR data were fitted to a simple exponential function as follows: y = alpha.e(-t/beta) + gamma, where y is SBP (mmHg) or UACR (mg/g creatinine); alpha is the extent of the SBP (mmHg)- or UACR (mg/g creatinine)-lowering effect; 13 (days) is the time-constant for SBP or UACR decrease; t is the number of days after the start of cilnidipine administration; and gamma is the finally stabilized SBP (mmHg) or UACR (mg/g creatinine).
    Results: Mean +/- SD morning SBP and UACR decreased by 20.4 +/- 11.4 mmHg and 15.2 +/- 13.1 mg/g creatinine, respectively, as determined by coefficient alpha. The mean SD time-constant for UACR decrease was significantly longer than that for BP decrease (43.5 +/- 22.9 vs 15.4 +/- 7.1 days). UACR reduction correlated with pre-treatment UACR values (correlation coefficient [R] = 0.88, p &lt; 0.01) but not with BP decrease.
    Conclusions: The present study demonstrated that cilnidipine reduced UACR in hypertensive patients with normal to marginally elevated UACR independent of its BP-lowering effect.

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  • A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9) expression by chondrocytes during endochondral ossification

    Kanae Kumagishi, Keiichiro Nishida, Tomoichiro Yamaai, Ryusuke Momota, Shigeru Miyaki, Satoshi Hirohata, Ichiro Naito, Hiroshi Asahara, Yoshifumi Ninomiya, Aiji Ohtsuka

    ARCHIVES OF HISTOLOGY AND CYTOLOGY   72 ( 3 )   175 - 185   2009.11

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    A disintegrin and metalloproteinase with thrombospondin motifs 9 (ADAMTS9) is known to influence aggrecan degradation in endochondral ossification, but its role has not been well understood. In the present study, in vitro gene expression of ADAMTS9 was investigated by RT-PCR in ATDC5 cells in which experimentally chondrogenic differentiation had been induced. We also investigated the protein localization and gene expression pattern of ADAMTS9 in the tibia growth plate cartilage of male mice in a day 1 neonate, 7-week-old young adult, and a 12-week-old adult by immunohistochemistry and in situ hybridization and compared the results with the expression of proliferating cell nuclear antigen (PCNA) and type X collagen for the identification of proliferative and hypertrophic chondrocyte phenotypes, respectively. We found the gene expression of ADAMTS9 by ATDC5 cells as a dual mode, both before the expression of type X collagen and after hypertrophic differentiation. The immunoreactivity of ADAMTS9 was observed in chondrocytes of proliferative and hypertrophic zones in the growth plate. The population of ADAMTS9 positive cells decreased with age. The results of the present study suggest that ADAMTS9 might have a role in aggrecan cleavage around the chondrocytes to allow chondrocyte proliferation and hypertrophy.

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  • Association of Increased Plasma Adipocyte Fatty Acid-binding Protein With Coronary Artery Disease in Men

    Shunichi Higashiya, Masayuki Doi, Kunio Nogami, Mutsumi Iwamoto, Akihisa Yumoto, Kou Takeda, Masayuki Ueeda, Toru Miyoshi, Satoshi Hirohata, Shozo Kusachi, Yoshifumi Ninomiya, Hiroshi Ito

    CIRCULATION   120 ( 18 )   S397 - S398   2009.11

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  • A Novel Cationic Protein Reduced Infracted Size and Protected Myocytes From Oxidative Stress Through Modification of Akt Signaling

    Shigeshi Kamikawa, Satoshi Hirohata, Syougo Watanabe, Takashi Ohtsuki, Toru Miyoshi, Hiroko Ogawa, Shozo Kusachi, Masaharu Senoo, Yoshifumi Ninomiya, Hiroshi Itoh

    CIRCULATION   120 ( 18 )   S888 - S889   2009.11

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  • ADAMTS-1 is an Endothelial Cell-specific Hypoxia-inducible Gene

    Satoshi Hirohata, Faruk O. Hatipoglu, Toru Miyoshi, Hiroko Ogawa, Masanari Obika, Shigeshi Kamikawa, Shozo Kusachi, Hiroshi Itoh, Yoshifumi Ninomiya

    CIRCULATION   120 ( 18 )   S1172 - S1172   2009.11

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  • Augmentation index is associated with B-type natriuretic peptide in patients with paroxysmal atrial fibrillation International journal

    Youko Kaji, Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Shigeshi Kamikawa, Kosuke Sakane, Tomoki Kitawaki, Shozo Kusachi, Kengo Fukushima Kusano, Hiroshi Ito

    HYPERTENSION RESEARCH   32 ( 7 )   611 - 616   2009.7

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    B-type natriuretic peptide (BNP) levels have been shown to be elevated in patients with paroxysmal atrial fibrillation (PAF); however, the underlying mechanisms have not been fully elucidated. Earlier, we reported that an increase in the augmentation index ( AI), which is an index of wave reflection and arterial stiffness, is associated with PAF. In this study, we investigate the relationship between the BNP level and AI in patients with PAF. We enrolled 92 patients with a history of PAF and 90 age- and gender-matched individuals without PAF. AI was calculated using applanation tonometry of the radial artery when all patients were on sinus rhythm. Plasma BNP levels were measured simultaneously. An arterial stiffness parameter, the cardio-ankle vascular index ( CAVI), was also evaluated. The increased AI in patients with PAF correlated with the elevation of the BNP level (r=0.47, P&lt;0.01). When PAF patients were classified into tertiles on the basis of the BNP level, the left atrial volume index, left ventricular mass index, AI and CAVI increased, and mitral annular e&apos; velocity (e&apos;), as an index of left ventricular diastolic pressure, decreased with BNP tertiles. AI was also associated with e&apos; and left ventricular mass index. Multiple regression analysis showed that the AI in PAF patients independently correlated with BNP levels. This study showed that AI was an independent correlate of the BNP level in PAF patients. Left ventricular diastolic dysfunction, which linked to an increase in arterial stiffness, may be involved in the elevated BNP level. Hypertension Research ( 2009) 32, 611-616; doi: 10.1038/hr.2009.62; published online 1 May 2009

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  • IDENTIFICATION OF NF-kappa B BINDING ELEMENTS IN HUMAN ADAMTS9 PROMOTER

    Kadir Demircan, Esra Gunduz, Mehmet Zeynel Cilek, Omer Faruk Hatipoglu, Kursat Oguz Yaykasli, Mehmet Gunduz, Yoshifum Ninomiya, Satoshi Hirohata

    IUBMB LIFE   61 ( 3 )   354 - 354   2009.3

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  • Relationship between activin A level and infarct size in patients with acute myocardial infarction undergoing successful primary coronary intervention International journal

    Toru Miyoshi, Satoshi Hirohata, Tadahisa Uesugi, Minoru Hirota, Hirornichi Ohnishi, Kunio Nogami, Kunihiko Hatanaka, Hiroko Ogawa, Shinichi Usui, Shozo Kusachi

    CLINICA CHIMICA ACTA   401 ( 1-2 )   3 - 7   2009.3

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    Background: Activin A, a member of the transforming growth factor-beta cytokine family, has been suggested to have a role in inflammation. We examined the serum level of activin A in patients with acute myocardial infarction (AMI) undergoing successful primary percutaneous coronary intervention (PCI).
    Methods: The subjects were 30 AMI patients, 20 stable angina pectoris (AP) patients and 20 normal subjects. The serum levels of activin A in AMI patients were measured before PCI and on days 1, 2, 7, and 14.
    Results: Activin A levels before PCI in AMI patients (557 +/- 255 pg/ml) showed a significantly higher value than those in AP patients (364 +/- 159 pg/ml) and control subjects (316 +/- 144 pg/ml). Increased serum activin A level before PCI was decreased on day 2, and then gradually re-elevated on days 7 and 14, The serum activin A level before PCI was correlated with log-transformed peak creatine kinase (CK) as a surrogate of infarct size (r=0.48, p=0.008). Stepwise multiple regression analysis demonstrated that the serum activin A level before PCI was an independent predictor of peak CK.
    Conclusions: The serum activin A level, increased in AMI, was positively correlated with peak CK and CK-MB levels which are measures of infarction size. (C) 2008 Elsevier B.V. All rights reserved.

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  • THE 3 '-UNTRANSLATED REGION OF THE ADAMTS1 REGULATES ITS EXPRESSION

    Omer Faruk Hatipoglu, Satoshi Hirohata, Kursat Oguz Yaykasli, Mehmet Zeynel Cilek, Kadir Demircan, Ryoko Shinohata, Shozo Kusachi, Yoshifumi Ninomiya

    IUBMB LIFE   61 ( 3 )   367 - 367   2009.3

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  • UTILIZATION OF ADAMTSI AS A NEW TOOL FOR DETECTING HYPOXIA

    Mehmet Zeynel Cilek, Satoshi Hirohata, Omer Faruk Hatipoglu, Kadir Demircan, Junko Inagaki, Tomoko Yonezawa, Toshikata Oohashi, Yoshifumi Ninomiya

    IUBMB LIFE   61 ( 3 )   357 - 358   2009.3

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  • ADAMTS1の血管新生阻害機能の解析 血管内皮細胞に対する影響

    高橋 克之, 廣畑 聡, 小比賀 真就, 三好 亨, 小川 弘子, 草地 省蔵, 二宮 善文

    日本薬学会年会要旨集   129年会 ( 3 )   218 - 218   2009.3

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  • Hyaluronan receptors involved in cytokine induction in monocytes Reviewed International journal

    Hitoshi Yamawaki, Satoshi Hirohata, Toru Miyoshi, Katsuyuki Takahashi, Hiroko Ogawa, Ryoko Shinohata, Kadir Demircan, Shozo Kusachi, Kazuhide Yamamoto, Yoshifumi Ninomiya

    GLYCOBIOLOGY   19 ( 1 )   83 - 92   2009.1

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    During inflammation, lower molecular weight fragments of hyaluronan accumulate, and this is known to be inflammatory and immune-stimulatory. In diseases such as inflammatory bowel disease, inflammatory cells bind to hyaluronan; however, the cellular response and molecular mechanism of hyaluronan-hyaluronan receptor interactions in mononuclear cells are not well understood. The expression of hyaluronan receptors in peripheral blood mononuclear cells (PBMC) was examined. PBMC were stimulated with lower and higher molecular weight hyaluronan (molecular weight 100-150 kDa and 2700 kDa) and the induction of proinflammatory cytokines (interleukin-6 (IL-6) and monocyte chemoattractant protein (MCP-1)) was compared by enzyme-linked immunoabsorbant assay (ELISA). Cells were coincubated with various signaling pathway inhibitors. In addition, neutralizing antibodies against CD44 and TLR4 were added and the effects on PBMC were investigated. Finally, mononuclear cells from CD44-null and toll-like receptor 4 (TLR4) mutant mice were both stimulated with lower molecular weight hyaluronan. Among the hyaluronan receptors, TLR4 and CD44 were markedly expressed on PBMC. Hyaluronan-stimulated PBMC enhanced the attachment to the extracellular matrix. Lower molecular weight hyaluronan induced IL-6 and MCP-1 production in PBMC, but high-molecular-weight hyaluronan did not induce IL-6 and MCP-1 production. An anti-CD44 antibody attenuated the induction of both IL-6 and MCP-1 in lower molecular weight hyaluronan-stimulated PBMC. In both TLR4 mutant and CD44-null mice, the induction of IL-6 by lower molecular weight hyaluronan stimulation was decreased. SB203580 completely abolished IL-6 production in both TLR4 mutant and CD44-null mononuclear cells, while PD98059 abolished IL-6 production in CD44-null mononuclear cells. Hyaluronan receptors, CD44 and TLR4, play distinct roles in cytokine induction in hyaluronan-stimulated mononuclear cells.

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  • Human eosinophil cationic protein enhances stress fiber formation in Balb/c 3T3 fibroblasts and differentiation of rat neonatal cardiomyocytes International journal

    Takayuki Fukuda, Miki Iwata, Midori Kitazoe, Takashi Maeda, David Salomon, Satoshi Hirohata, Katsuyuki Tanizawa, Shun'ichi Kuroda, Masaharu Seno

    GROWTH FACTORS   27 ( 4 )   228 - 236   2009

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    We found that eosinophil cationic protein (ECP) stimulated the growth of mouse Balb/c 3T3 fibroblasts. ECP-treated 3T3 cells were more flattened and exhibited enhanced stress fiber formation. The enhancement of cytoskeleton after addition of recombinant ECP appeared stable and was able to inhibit disassembly of actin filaments that was induced by fibroblast growth factor-2. The ROCK inhibitor, Y-27632, abrogated this enhancement on stress fiber formation that was induced by ECP indicating the involvement of Rho/ROCK signaling pathway. The effect of ECP was assessed on the differentiation of primary cardiomyocytes derived from rat neonatal heart since the development of actin filaments is significantly related with organization of stress fibers. As the result, both beating rate and the expression of cardiac muscle specific markers such as atrial natriuretic factor were enhanced in the presence of ECP. Thus ECP may also function as a cardiomyocyte differentiation factor.

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  • Increased Augmentation Index of the Radial Pressure Waveform in Patients with Paroxysmal Atrial Fibrillation International journal

    Masayuki Doi, Toru Miyoshi, Satoshi Hirohata, Akihiro Iwabu, Youkou Tominaga, Youko Kaji, Shigeshi Kamikawa, Kosuke Sakane, Tomoki Kitawaki, Kengo F. Kusano, Shozo Kusachi

    CARDIOLOGY   113 ( 2 )   138 - 145   2009

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    Objective: The augmentation index, a marker of wave reflection, has been reported to reflect vascular properties and to determine left ventricular (LV) characteristics. We investigated the relationship between the augmentation index and paroxysmal atrial fibrillation (AF). Methods: A total of 244 outpatients (122 patients with paroxysmal AF and 122 age-, and gender-matched controls without paroxysmal AF) were examined during sinus rhythm. The augmentation index was calculated from the radial arterial waveform using applanation tonometry methods. Results: After adjusting for age, gender, heart rate, and medications, the augmentation index was significantly higher in patients with paroxysmal AF than in subjects without paroxysmal AF (means +/- SE: 88.9 +/- 1.0 and 81.8 +/- 1.0%, respectively; p &lt; 0.001). In all subjects, an increase in the augmentation index was significantly correlated with LV hypertrophy and left atrial enlarge ment. Multiple logistic analysis revealed that an increase in the augmentation index was significantly related with paroxysmal AF, and the adjusted odds ratio of paroxysmal AF was approximately 1.8 for each 10% augmentation index increase (p &lt; 0.01). Conclusion: An increase in the augmentation index was independently associated with paroxysmal AF. This result suggests that enhanced wave reflection may be related to the development of AF. Copyright (C) 2008 S. Karger AG, Basel

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  • Serum N-3 Polyunsaturated Fatty Acid Levels Correlate With the Extent of Coronary Plaques and Calcifications in Patients With Acute Myocardial Infarction

    Masayuki Ueeda, Takenori Doumei, Yoichi Takaya, Ryoko Shinohata, Yusuke Katayama, Nobuhiko Ohnishi, Atsushi Takaishi, Toru Miyoshi, Satoshi Hirohata, Shozo Kusachi

    CIRCULATION JOURNAL   72 ( 11 )   1836 - 1843   2008.11

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    Background The relationship between serum fatty acid levels and the extent of coronary plaques and calcification was examined in patients with acute myocardial infarction (AMI).
    Methods and Results The serum levels of the n-3 polyunsaturated fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) and the n-6 polyunsaturated fatty acids (arachidonic acid (AA) and dihomo-(gamma-linolenic acid (DGLA)) were determined using gas chromatography on admission of 95 consecutive patients with their first AMI and 17 controls. Using multidetector-row computed tomography, soft plaques and calcification lesions were scored according to the extent of coronary involvement. Serum logarithmic transformed (log) EPA and logDHA levels were inversely correlated with soft plaque scores (r=-0.546, p &lt; 0.0001 and r= -0.377, p &lt; 0.0001, respectively). Serum logAA and logDGLA levels were not significantly correlated with soft plaque scores. Serum logEPA and logDHA levels were significantly, but weakly, correlated with calcification scores. Multivariate analysis with clinical characteristics and risk factors selected serum n-3 polyunsaturated fatty acid levels as independent factors associated with the extent of coronary soft plaques.
    Conclusion The present study demonstrates a significant correlation between serum n-3 polyunsaturated fatty acid levels and the extent of coronary soft plaques and calcification in AMI patients. (Circ J 2008; 72: 1836-1843)

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  • Serum Adipocyte Fatty Acid-Binding Protein Levels are Independently Associated with Coronary Atherosclerosis

    Toru Miyoshi, Atsushi Hirohata, Shinichi Usui, Keizo Yamamoto, Kazuyoshi Hina, Satoshi Hirohata, Shozo Kusachi, Yoshifumi Ninomiya, Kengo F. Kusano

    CIRCULATION   118 ( 18 )   S470 - S470   2008.10

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  • The Impact of Increased Augmentation Index of Radial Pressure Waveform on Paroxysmal Atrial Fibrillation

    Youko Kaji, Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Tadahisa Uesugi, Shigeshi Kamikawa, Kosuke Sakane, Shozo Kusachi, Kengo F. Kusano

    CIRCULATION   118 ( 18 )   S730 - S730   2008.10

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  • Prone position is essential for detection of pulmonary vein pseudostenosis by enhanced multidetector computed tomography in patients who undergo pulmonary vein isolation

    Hirosuke Yamaji, Kazuyoshi Hina, Hiroshi Kawamura, Takashi Murakami, Masaaki Murakami, Keizo Yamamoto, Atsushi Hirohata, Toru Miyoshi, Satoshi Hirohata, Shozo Kusachi

    CIRCULATION JOURNAL   72 ( 9 )   1460 - 1464   2008.9

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    Background pulmonary vein (PV) stenosis is a major complication of PV isolation (PVI) by catheter ablation, so in the present study the optimal position for detecting PV stenosis on enhanced multidetector computed tomography (MDCT) image acquisition was determined.
    Methods and Results The 64-slice enhanced MDCT was carried out before and after PVI in 116 consecutive patients with atrial fibrillation while they were in the prone position, as well as while supine. The supine position MDCT image showed &gt; 50% diameter stenosis of the PV in 11 (9%) patients before PVI (% diameter stenosis: mean 55 +/- 4%, range 51-65%). Greater than &gt; 50% diameter stenosis was seen in the left inferior PV in all 11 patients. The prone position attenuated the PV stenosis findings in the MDCT images in all 11 patients (mean 9 +/- 6%, range 2-18%). Stenosis visualized on images acquired in the supine position was, therefore, concluded to be pseudostenosis caused by descending aorta compression. At 3 months after PVI, no significant changes in PV diameter were observed in these 11 patients.
    Conclusion The present study demonstrated that the prone position is essential for eliminating PV pseudostenosis observed oil supine-position enhanced MDCT images. The results also indicate that preexisting PV organic stenosis is rare.

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  • Association of corrected QT dispersion with symptoms improvement in patients receiving cardiac resynchronization therapy

    Kazuyoshi Hina, Hiroshi Kawamura, Takashi Murakami, Keizo Yamamoto, Hirosuke Yamaji, Masaaki Murakami, Satoshi Hirohata, Hiroko Ogawa, Kohsuke Sakane, Shozo Kusachi

    HEART AND VESSELS   23 ( 5 )   325 - 333   2008.9

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    Cardiac resynchronization therapy (CRT) is theoretically expected to affect repolarization as well as depolarization. We studied the effects of CRT on corrected QT (QTc) dispersion in association with symptomatic improvement. QTc dispersion was analyzed in 26 consecutive patients (67 +/- 6 years old, 18 men and 8 women) who underwent CRT. CRT responders and nonresponders were defined as patients showing and not showing &gt;= 1 class New York Heart Association symptomatic improvement 3 months after CRT, respectively. QTc interval, QRS width, and QTc dispersion were measured automatically from digital data using an analyzing system. There were 18 CRT responders and 8 nonresponders among the patients. CRT responders showed significantly larger QTc dispersion than CRT nonresponders before CRT (102 +/- 26 vs 40 +/- 12 ms, P &lt; 0.01). A significant decrease in QTc dispersion by CRT was observed in responders (102 +/- 26 to 52 +/- 15 ms, P &lt; 0.01). In contrast, QTc dispersion was not decreased by CRT in nonresponders (40 +/- 12 to 39 +/- 11 ms, not significant). The difference observed before CRT was thus abolished after CRT (52 +/- 15 vs 39 +/- 11 ms, not significant). Baseline values and changes in QRS width or QTc, as well as asynchrony of wall motion determined by tissue Doppler imaging, were not different between CRT responders and nonresponders before CRT. The present study with a small number of patients shows the potential utility of QTc dispersion for distinguishing CRT responders from CRT nonresponders before CRT, and warrants further study with a greater number of patients.

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  • Higher incidence and serum levels of minor cardiac biomarker elevation in sirolimus-eluting stent (Cypher) than bare metal stent implantations Reviewed International journal

    Tetsushi Seitou, Masaaki Murakami, Issei Komatsubara, Hiroshi Kawamura, Keizo Yamamoto, Kazuyoshi Hina, Satoshi Hirohata, Ryoko Shinohata, Yoshifumi Ninomiya, Shozo Kusachi

    CORONARY ARTERY DISEASE   19 ( 2 )   63 - 69   2008.3

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    Objectives Minor cardiac biomarker elevation after percutaneous coronary intervention has long-term prognostic significance. The sirolimus-eluting stent (Cypher) has been reported to require high postinflation pressure for optimal implantation. We examined the incidence of minor cardiac biomarker elevation induced by Cypher implantation.
    Methods We measured the serum concentration of cardiac troponin-I (cTnl) 24 h after stenting and those of creatine kinase isoenzyme MB and creatine kinase before, immediately after, and 6, 12 and 24 h after implantation in patients who underwent Cypher stent (CS group; n = 53) or bare metal stent (BMS group; n = 57) implantation.
    Results No significant difference in clinical background was observed between the two groups. When a cutoff cTnl value of 0.50ng/ml was used, the CS group showed a significantly higher incidence of cTnl elevation (35.8%, 19/53) than the BMS group (14.0%, 8/57) (P&lt;0.05). Similarly, the incidence of cTnl &gt;= 0.03 ng/ml tended to be higher in the CS group (88.7%, 47/53) than in the BMS group (73.7%, 42/57: 0.05&lt;P&lt;0.10). Furthermore, the CS group showed significantly higher cTnl levels than the BMS group (1.32 +/- 2.38 vs. 0.34 +/- 0.91 ng/ml. P&lt; 0.001). Essentially, similar results were obtained for serum creatine kinase isoenzyme MB and creatine kinase. Among clinical, lesion and procedural characteristics, postinflation pressure for stenting was significantly higher only in the CS group (18.2 +/- 2.8 atm) than in the BMS group (14.0 +/- 2.7 atm) (P&lt; 0.001).
    Conclusions The results demonstrated that CS implantation increases the incidence of minor cardiac biomarker elevation compared with BMS. The difference in postinflation pressure could account for the results.

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  • Increased augmentation index of radial pulse wave in patients with paroxysmal atrial fibrillation

    Toru Miyoshi, Masayuki Doi, Youko Kaji, Satoshi Hirohata, Shigeshi Kamikawa, Shozo Kusachi, Tohru Ohe

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   51 ( 10 )   A304 - A304   2008.3

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  • Increased blood pressure levels relative to subjective feelings of intensity of exercise determined with the borg scale in male patients with hypertension International journal

    Eriko Mayumi, Aya Nishitani, Yoko Yuki, Takaaki Nakatsu, Shinji Toyonaga, Keiichi Mashima, Hiroko Ogawa, Satoshi Hirohata, Shinichi Usui, Ryoko Shinohata, Kousaku Sakaguchi, Shozo Kusachi

    CLINICAL AND EXPERIMENTAL HYPERTENSION   30 ( 3-4 )   191 - 201   2008

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    We examined the hemodynamic responses to exercise and symptoms in 37 male patients with untreated essential hypertension, and compared the findings with those in 32 age-matched healthy male volunteers by performing a graded symptom-limited exercise test using a bicycle ergometer. The subjective feeling of intensity of exercise was determined using the Borg scale. In the relationship between Borg scores and blood pressure (BP), patients with hypertension showed higher systolic BP and diastolic BP relative to the Borg scores than the controls. Consequently, patients with hypertension showed significantly higher systolic BP with Borg scores &lt;= 3 (subjective symptoms &lt;= moderately hard) than the controls (177.8 +/- 27.0 vs. 143.7 +/- 17.9 mmHg, p 0.0001). Similarly, significantly higher diastolic BP with Borg scores 3 was observed in patients with hypertension than in the controls (101.6 +/- 12.0 vs. 82.6 +/- 11.6 mmHg, p &lt; 0.0001). The pulse pressure with Borg scores 3 was also significantly higher in patients with hypertension than in the controls (76.2 +/- 20.6 vs. 61.0 +/- 13.6 mmHg, p &lt; 0.0001). Hypertensive patients showed a decrease in the high-frequency power of heart rate variability at initial low-load exercise. In conclusion, the present study revealed that there was a greater BP response relative to the Borg score in patients with hypertension than in the controls. Autonomic nerve activity may contribute to some extent to these different relations. A determination of the relationship between the subjective feeling of intensity of the exercise and BP levels caused by a given intensity of load is essential before exercise training in patients, at least in males, with hypertension to avoid increasing the risk of cardiovascular events in association with excessive exercise training.

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  • OA軟骨破壊におけるアグリカナーゼの役割

    鉄永智紀, 広畑 聡, 西田圭一郎

    関節外科   27   221 - 227   2008

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  • Association of new arterial stiffness parameter, the cardio-ankle vascular index, with left ventricular diastolic function

    Kosuke Sakane, Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Youko Kaji, Shigeshi Kamikawa, Hiroko Ogawa, Kunihiko Hatanaka, Tomoki Kitawaki, Shozo Kusachi, Kazuhide Yamamoto

    Journal of Atherosclerosis and Thrombosis   15 ( 5 )   261 - 268   2008

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    Aim: Pulse wave velocity has been used as an index of aortic stiffness. Recently, the cardio-ankle vascular index (CAVI), which reflects the stiffness of the aorta independently of blood pressure, has been developed. In this study, we analyzed the relationship between CAVI and left ventricular (LV) diastolic dysfunction. Methods: A total of 119 patients were referred for echocardiography to evaluate ventricular function. Patients with reduced systolic function were excluded. Patients were divided on the basis of normal or reduced LV diastolic function determined by echocardiography. CAVI was measured using an automatic waveform analyzer. Results: CAVI was significantly higher in patients with reduced LV diastolic function than those with normal LV diastolic function (9.0 ± 1.1 and 8.5 ± 1. 1, p= 0.009). Multiple linear regression analysis revealed that CAVI was independently associated with the ratio of peak early diastolic velocity to peak atrial diastolic velocity an left atrial diameter. When patients were classified on the basis of CAVI quartiles, multiple logistic regression analysis demonstrated that the highest quartile of CAVI showed an increased odds ratio for the presence of IV diastolic dysfunction. Conclusion: The present study revealed that an increased CAVI was independently associated with LV diastolic dysfunction in patient's with preserved systolic function.

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  • Serum activin a level is associated with infarct size in patients with acute myocardial infarction who undergo successful primary percutaneous coronary intervention

    Toru Miyoshi, Satoshi Hirohata, Tadahisa Uesugi, Minoru Hirota, Hiromichi Ohnishi, Kunio Nogami, Shozo Kusachi, Tohru Ohe

    CIRCULATION   116 ( 16 )   711 - 711   2007.10

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  • Safety of and tolerance to adenosine infusion for myocardial perfusion single-photon emission computed tomography in a Japanese population

    Kunihiko Hatanaka, Masayuki Doi, Satoshi Hirohata, Shigeshi Kamikawa, Yoko Kaji, Tsutomu Katoh, Shozo Kusachi, Yoshifumi Ninomiya, Tohru Ohe

    CIRCULATION JOURNAL   71 ( 6 )   904 - 910   2007.6

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    Background Adenosine has been available for use in myocardial perfusion single-photon emission computed tomography (SPECT) in Japan since 2005. The purpose of this study was to evaluate the safety of and tolerance to thallium-201 myocardial perfusion SPECT with intravenous adenosine infusion in Japanese patients with suspected coronary artery disease.
    Methods and Results Two hundred and six consecutive patients who underwent an adenosine infusion (120 mu g center dot kg(-1) center dot min(-1)) SPECT at Sumitomo Besshi Hospital (Niihama, Japan) were investigated. The effects of adenosine infusion were monitored for each patient. A coronary angiography was performed in 81 patients. Adenosine infusion significantly decreased blood pressure and increased heart rate. Adverse reactions were observed in 161 patients (78.2%). Most reactions were transient, disappearing soon after the termination of adenosine infusion. No serious adverse reactions, such as acute myocardial infarction or death, occurred. Adenosine infusion was terminated in 3 patients (1.5%) because of near syncope or sustained 2:1 atrioventricular block. Electrocardiographic changes occurred in 15 patients (7.3%). Self-assessed scoring after SPECT showed that the patients were very tolerant (74.6% of 177 patients) of adenosine infusion myocardial SPECT. The sensitivity and specificity were 75.0% and 69.7%, respectively.
    Conclusions Adenosine infusion myocardial SPECT is safe and well tolerated in the Japanese population, despite the frequent occurrence of minor adverse reactions.

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  • がん細胞株におけるADAMTS1の発現レベルの検討

    メフメット・ゼネユル・チレッキ, 廣畑 聡, カディール・デミルジャン, オメル・ファルク・ハティポール, 小川 弘子, 米澤 朋子, 草地 省蔵, 大橋 俊孝, 二宮 善文

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   39回・54回   144 - 144   2007.5

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  • ADAMTS1は内皮細胞特異的に細胞浸潤を抑制する

    廣畑 聡, 小比賀 真就, 小川 弘子, 三好 亨, Cilek Mehmet Zeynel, Demircan Kadir, Hatipoglu Omer Faruk, 草地 省蔵, 二宮 善文

    日本結合組織学会学術大会・マトリックス研究会大会合同学術集会プログラム・抄録集   39回・54回   134 - 134   2007.5

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  • Development of an automatic Doppler flow signal detection system: variability of pulmonary and aortic peak flow velocity

    Chiho Morita, Takaaki Nakatsu, Shozo Kusachi, Tomoki Kitawaki, Shinichi Usui, Kazuo Tobe, Shinji Toyonaga, Hiroko Ogawa, Satoshi Hirohata, Yasushi Shiratori

    JOURNAL OF MEDICAL ULTRASONICS   34 ( 1 )   37 - 42   2007

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    Purpose. Automatic Doppler flow signal detection systems can provide beat-to-beat information for large blood vessels. We have developed new equipment for automatic measurement of Doppler flow signals. The reliability of the system was examined, and the variability of aortic and pulmonary peak flow velocity was determined.
    Methods. We measured peak flow velocity using a newly developed system in healthy volunteers and patients with atrial fibrillation. Analysis of variability of peak flow velocity was performed with maximal entropy methods.
    Results. In Bland-Altman plots, the mean and standard deviation (SD) of differences in aortic peak flow velocities between the automatic and manual measurements were 0.22 +/- 0.75cm/s and 0.85 +/- 0.38cm/s, respectively, in five normal volunteers. Moreover, less than 5% of the plotted points were beyond 2 SD of the differences. Furthermore, good reproducibility was demonstrated using Bland-Altman plots and Pearson&apos;s correlation analysis. Identical reliability was obtained in patients with atrial fibrillation. The same results were obtained for pulmonary peak flow velocity. In five healthy subjects, aortic and pulmonary peak flow showed standard deviations of 7.2 +/- 2.4 and 3.8 +/- 0.6cm/s, respectively, and coefficients of variation of 6.1% +/- 1.0% and +/- 1.1%, respectively, in time-domain variability. Similarly, frequency-domain variability was obtained for both peak flow velocities.
    Conclusion. The present study demonstrated the reliability of a newly developed automatic Doppler flow signal detection system. Using this system, the present study demonstrated for the first time aortic and pulmonary peak flow velocity variability. The present analytical methods may have considerable potential for studying aortic and/or pulmonary flow variability in connection with cardiac performance and prognosis of cardiac disease.

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  • Decreased serum levels of interferon gamma inducible protein 10 (IP-10) in acute myocardial infarction patients after successful primary percutaneous coronary intervention are associated with a smaller infarct size

    Satoshi Hirohata, Kazuya Koten, Shinichi Usui, Hiroko Ogawa, Hitoshi Yamawaki, Masanari Obika, Mutsurni Iwamoto, Yasushi Shiratori, Shozo Kusachi, Tohru Ohe

    CIRCULATION   114 ( 18 )   744 - 744   2006.10

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  • The balance of n6/n3 polyunsaturated fatty acid (PUFAs) is an important determinant factor of prognosis after acute myocardial infarction

    Takenori Domei, Masayuki Ueeda, Yoichi Takaya, Nobuhiko Ohnishi, Atsushi Takaishi, Masanobu Imai, Satoshi Hirohata, Shozo Kusachi, Toru Ohe

    CIRCULATION   114 ( 18 )   463 - 463   2006.10

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  • Statin treatment accelerated neovessel formation in the border zone of the infarcted heart: Architectural study of vascular casts by scanning electron microscopy

    Mutsumi Iwamoto, Satoshi Hirohata, Masahiko Maruyama, Kunihiko Hatanaka, Hiroko Ogawa, Yasushi Shiratori, Shozo Kusachi, Tohru Ohe

    CIRCULATION   114 ( 18 )   206 - 206   2006.10

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  • Tumor-specific expression of the RGD-alpha 3(IV)NC1 domain suppresses endothelial tube formation and tumor growth in mice International journal

    Toru Miyoshi, Satoshi Hirohata, Hiroko Ogawa, Masayuki Doi, Masanari Obika, Tomoko Yonezawa, Yoshikazu Sado, Shozo Kusachi, Satoru Kyo, Seiji Kondo, Yasushi Shiratori, Billy G. Hudson, Yoshifumi Ninomiya

    FASEB JOURNAL   20 ( 11 )   1904 - +   2006.9

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    Angiogenesis plays an essential role in tumor growth. This study investigated expression of the noncollagenous domain of alpha 3(IV) collagen (alpha 3(IV) NC1) transduced into tumors and its inhibition of tumor growth. We hypothesized that if a human telomerase reverse transcriptase (hTERT) promoter-driven RGD motif containing alpha 3(IV) NC1 (hTERT/ RGD-alpha 3(IV) NC1) were expressed in telomerase-expressing tumor cells, it would inhibit tumor growth by its anti-angiogenic property. Adenoviral transduction of hTERT/ RGD-alpha 3(IV) NC1 expressed RGD-alpha 3(IV) NC1 in hTERT-positive tumor cell lines. However, hTERT/ RGD-alpha 3(IV) NC1 did not express RGD-alpha 3(IV) NC1 in hTERT-negative cells such as keratinocytes and fibroblasts. The secreted RGD-alpha 3(IV) NC1 in the conditioned medium from tumor cells inhibited cell proliferation as well as tube formation in cultured endothelial cells, but had no effect on other types of cells. In an in vivo model, adenoviral hTERT/ RGD-alpha 3(IV) NC1 gene therapy showed limited expression of RGD-alpha 3(IV) NC1 in tumors and resulted in a significant decrease of vessel density in tumors. The growth of subcutaneous (s. c.) tumors in nude mice was significantly suppressed by treatment with hTERT/ RGD-alpha 3(IV) NC1. In addition, long-term inhibition of tumor growth was achieved by intermittent administration of hTERT/ RGD-alpha 3(IV) NC1. In conclusion, our findings demonstrate that tumor-specific antiangiogenic gene therapy utilizing RGD-alpha 3(IV) NC1 under the hTERT promoter inhibited angiogenesis in tumors, resulting in an antitumor effect.

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  • ヒト末梢血単球成分におけるヒアルロン酸の炎症反応誘導機構の解析

    山脇 均, 廣畑 聡, 小川 弘子, 二宮 善文, 草地 省蔵, 白鳥 康史, 大江 透

    日本動脈硬化学会総会プログラム・抄録集   38回   240 - 240   2006.7

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  • Coronary pressure measurement to identify the lesion requiring percutaneous coronary intervention in equivocal tandem lesions International journal

    Minoru Hirota, Kohichiro Iwasaki, Keizo Yamamoto, Shozo Kusachi, Kazuyoshi Hina, Satoshi Hirohata, Masaaki Murakami, Shigeshi Kamikawa, Takashi Murakami, Yasushi Shiratori

    CORONARY ARTERY DISEASE   17 ( 2 )   181 - 186   2006.3

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    No reliable methods are available for determining application of percutaneous coronary intervention for treatment of equivocal tandem lesions. We investigated whether coronary pressure measurement is useful for determining the lesion that requires percutaneous coronary intervention in tandem lesions.
    We measured coronary pressure in 72 consecutive patients with tandem lesions. Myocardial fractional flow reserve (FFRmyo) was obtained as the ratio of coronary pressure distal to the lesion/aortic pressure under maximal hyperemia. If the FFRmyo across the tandem lesions was &gt;= 0.75, we deferred percutaneous coronary intervention for the lesion. When the tandem lesions showed FFRmyo &lt; 0.75, percutaneous coronary intervention was performed on the lesion that showed angiographically higher stenosis. When FFRmyo was &lt; 0.75 after one-lesion percutaneous coronary intervention, this intervention was carried out on the remaining lesion.
    We deferred percuatneous coronary intervention for 26 patients (36.1%), and performed percutaneous coronary intervention in 46 patients (63.8%). We performed percutaneous coronary intervention for one lesion in 19 patients (26.4%) and for both lesions in 27 patients (37.5%). Among patients, in whom percutaneous coronary intervention was deferred, only two patients (7.7%) required target lesion revascularization during the follow-up period. This rate was not higher than that in the 46 patients who underwent percutaneous coronary intervention for one or two lesions (six patients, 13.0%). Similarly, the target lesion revascularization in lesions with initially deferred percuataneous coronary intervention (5.6%, 4/71 lesions) was not higher than that in lesions with percutaneous coronary intervention (15.1%, 11/73 lesions). Major cardiac events, cardiac death and acute myocardial infarction, did not occur in patients with deferred percutaneous coronary intervention during the follow-up period.
    Our results clearly showed that coronary pressure measurement was clinically useful for identifying equivocal tandem lesions requiring percutaneous coronary intervention.

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  • Nicorandil reduces the incidence of minor cardiac marker elevation after coronary stenting International journal

    M Murakami, K Iwasaki, S Kusachi, K Hina, M Hirota, S Hirohata, S Kamikawa, M Sangawa, K Yamamoto, Y Shiratori

    INTERNATIONAL JOURNAL OF CARDIOLOGY   107 ( 1 )   48 - 53   2006.2

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    Background: Minor cardiac marker elevation after percutaneous coronary intervention has long-term prognostic significance. We examined whether nicorandil, a nicotinamide-nitrate ester, reduces the incidence of minor cardiac marker elevation after coronary stenting.
    Methods: Patients (n=192) undergoing coronary stenting were randomly assigned to receive nicorandil (nicorandil group, n=91) or vehicle (control group, n=101). Nicorandil (2 mu g/kg/min, intravenously) was administered immediately after the patients were transfer-red into the catheterization laboratory and continued for 6 h. We measured the serum concentrations of creatine kinase isoenzyme MB (CK-MB) before, immediately after, and 6, 12, and 24 h after the procedure, and those of cardiac troponin T (cTnT) 24 h after the procedure.
    Results: There was no significant difference in clinical background between the 2 groups. The nicorandil group showed a significantly lower incidence of CK-MB elevation (&gt; 1 x upper limit of control range, 20 IU/l) than the control group (8.8% vs 21.8%,p &lt; 0.05). The levels of serum CK-MB in the nicorandil group were significantly lower than those in the control group (13.4+5.7 vs 16.5 +/- 9.7 IU/l, p &lt; 0.01). Similarly, the nicorandil group showed a significantly lower incidence of cTnT elevation [&gt; 1 x (0.1 ng/ml) or &gt; 2x (0.2 ng/ml)] upper limit of control range than the control group (14.3% vs 26.7%, p &lt; 0.05, or 7.7% vs 17.8%,p &lt; 0.05). Serum cTnT levels were also significantly lower in the nicorandil group than in the control group (0.05 +/- 0.10 vs 0.15 +/- 0.36 ng/ml, p &lt; 0.05).
    Conclusions: The results demonstrated that nicorandil reduces minor cardiac marker elevation after coronary stenting. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

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  • Versican is induced in infiltrating monocytes in myocardial infarction International journal

    K Toeda, K Nakamura, S Hirohata, OF Hatipoglu, K Demircan, H Yamawaki, H Ogawa, S Kusachi, Y Shiratori, Y Ninomiya

    MOLECULAR AND CELLULAR BIOCHEMISTRY   280 ( 1-2 )   47 - 56   2005.12

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    Versican, a large chondroitin sulfate proteoglycan, plays a role in conditions such as wound healing and tissue remodelling. To test the hypothesis that versican expression is transiently upregulated and plays a role in the infarcted heart, we examined its expression in a rat model of myocardial infarction. Northern blot analysis demonstrated increased expression of versican mRNA. Quantitative real-time RT-PCR analysis revealed that versican mRNA began to increase as early as 6 h and reached its maximal level 2 days after coronary artery ligation. Versican mRNA then gradually decreased, while the mRNA of decorin, another small proteoglycan, increased thereafter. Versican mRNA was localized in monocytes, as indicated by CD68-positive staining, around the infarct tissue. The induction of versican mRNA was accelerated by ischemia/reperfusion (I/R), which was characterized by massive cell infiltration and enhanced inflammatory response. To examine the alteration of versican expression in monocytes/macrophages, we isolated human peripheral blood mononuclear cells and stimulated them with granulocyte/macrophage colony-stimulating factor (GM-CSF). Stimulation of mononuclear cells with GM-CSF increased the expression of versican mRNA as well as cytokine induction. The production of versican by monocytes in the infarct area represents a novel finding of the expression of an extracellular matrix gene by monocytes in the infarcted heart. We suggest that upregulation of versican in the infarcted myocardium may have a role in the inflammatory reaction, which mediates subsequent chemotaxis in the infarcted heart.

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  • Coronary pressure measurement to determine treatment strategy for equivocal left main coronary artery lesions

    S Suemaru, K Iwasaki, K Yamamoto, S Kusachi, K Hina, S Hirohata, M Hirota, M Murakami, S Kamikawa, T Murakami, Y Shiratori

    HEART AND VESSELS   20 ( 6 )   271 - 277   2005.11

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    It is often hard to select a treatment strategy for equivocal left main coronary artery (LMCA) disease. We investigated the usefulness of coronary pressure (CP) measurement for determining the treatment strategy in intermediate LMCA disease. We measured CP in 15 consecutive patients with equivocal LMCA disease (age 67.6 +/- 7.5 years, 14 males). Myocardial fractional flow reserve (FFRmyo) was obtained as the ratio of CP distal to the lesion/aortic pressure under maximal coronary dilation. Patients with FFRmyo &gt;= 0.75 and &lt; 0.75 received medical therapy and coronary artery bypass grafting (CABG), respectively, and were followed up for 32.5 +/- 9.7 (20-47) months. Eight patients received medical therapy and 7 patients underwent CABG in accordance with the FFRmyo criteria noted above. FFRmyo of the LMCA was 0.91 +/- 0.01 and 0.61 +/- 0.03 in patients who received medical and surgical therapy, respectively. Neither reference vessel diameter, minimal lumen diameter, nor percent diameter stenosis was significantly different between patients who received medical and surgical therapy. During the follow-up period, no patients with medical therapy showed symptoms due to the LMCA lesion. Similarly, 5 of 7 patients with CABG showed improvement of symptoms and the remaining 2 patients were hospitalized with congestive heart failure. No cardiac death was recorded in the patients with medical or surgical therapy. In conclusion, the present results clearly demonstrated that CP is clinically useful for determining the treatment strategy for equivocal LMCA lesions but coronary angiography is not.

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  • Frequent deletion and down-regulation of ING4, a candidate tumor suppressor gene at 12p13, in head and neck squamous cell carcinomas International journal

    M Gunduz, H Nagatsuka, K Demircan, E Gunduz, B Cengiz, M Ouchida, H Tsujigiwa, E Yamachika, K Fukushima, L Beder, S Hirohata, Y Ninomiya, K Nishizaki, K Shimizu, N Nagai

    GENE   356 ( 1-2 )   109 - 117   2005.8

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    We previously showed two members of the ING family, ING1 and ING3 as a tumor suppressor gene in head and neck cancer. Progress in human genome sequencing provided additional information of the new members of the ING family genes. ING4 is localized to chromosome 12p13.31 region and harbors the PHD domain highly homologous among ING family proteins. We analyzed loss of heterozygosity at 12p12-13 region in 50 head and neck squamous cell carcinomas by using six highly polymorphic microsatellite markers and found allelic loss in 66% (33/50) of the informative cases. To clarify the role of ING4 in head and neck carcinogenesis, we first checked mutation status in tumor samples. As mutation of the ING4 gene was not found in head and neck cancers, we examined the mRNA expression level. Quantitative real-time RT-PCR analysis demonstrated decreased expression of ING4 mRNA in 76% of primary tumors as compared with that of matched normal samples. Since p53 dependent pathways of other ING family members have been shown, we examined p53 mutation status and compared with ING4 mRNA expression in tumor samples. However, no such direct relationship has been detected. In conclusion, frequent deletion and decreased mRNA expression of ING4 suggested it as a class two tumor suppressor gene and may play an important role in head and neck cancer. (c) 2005 Elsevier B.V. All rights reserved.

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  • バーシカンはラット心筋梗塞において一時的に上昇し,その発現は再灌流傷害により増強する

    廣畑 聡, 小川 弘子, 山脇 均, 小比賀 真就, 草地 省蔵, 白鳥 康史, 大江 透, 二宮 善文

    日本動脈硬化学会総会プログラム・抄録集   37回   197 - 197   2005.7

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  • Significant correlation of recruitable coronary collateral blood flow determined by coronary wedge pressure with ST-segment elevation during coronary occlusion International journal

    S Karnikawa, K Iwasaki, K Yamamoto, S Kusachi, K Hina, S Hirohata, M Murakami, M Hirota, T Murakami, Y Shiratori

    CORONARY ARTERY DISEASE   16 ( 4 )   231 - 236   2005.6

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    Objectives Quantitative assessment of coronary collateral blood flow can be archived by measuring coronary pressure. We studied the relationships between recruitable coronary collateral blood flow and electrocardiographic changes during percutaneous coronary intervention (PCI).
    Methods We measured coronary pressure during coronary occlusion with PCI in 119 patients with left anterior descending coronary artery stenosis. During balloon inflation, the electrocardiogram was continuously recorded. The ST-segment elevation in the most elevated lead was defined as MaxST and the sum of the maximal ST elevation in leads V2-V4 was defined as Sigma ST. Fractional collateral flow (Qc/Q(N)) was calculated as the coronary wedge pressure divided by the mean aortic pressure. Myocardial ischemia was defined as an ST-segment shift &gt; 0.1 mV in any of the V2, V3 or V4 leads.
    Results A significant relationship between Qc/Q(N) and MaxST was observed (r= -0.455, P &lt; 0.0001). Similarly, Qc/Q(N) was significantly correlated with Sigma ST (r= - 0.477, P &lt; 0.0001). The receiver operating characteristic curve showed that a cut-off value of 0.27 for Qc/Q(N), with sensitivity of 71.4% and specificity of 76.2%, was an indicator of electrophysiologically sufficient recruitable coronary collateral blood flow for prevention of ischemia during coronary obstruction. Qc/Q(N) values during the first, second, third and fourth inflation were not significantly different.
    Conclusions Qc/Q(N) could be clinically useful for determining whether there is electrophysiologically sufficient recruitable coronary collateral blood flow for prevention of ischemia during coronary obstruction. Repeat transient coronary occlusion during PCI did not lead to increased collateral blood flow. (c) 2005 Lippincott Williams & Wilkins.

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  • 5) Identification and Characterization of a novel rat link protein gene : Lp3/Hapln3

    小川 弘子, 廣畑 聡, 三好 亨, 村上 充, 白鳥 康史, 大橋 俊孝, 二宮 善文, 草地 省蔵, 佐田 政隆

    Circulation journal : official journal of the Japanese Circulation Society   68 ( 0 )   938 - 938   2004.10

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  • Dynamic induction of ADAMTS1 gene in the early phase of acute myocardial infarction International journal

    K Nakamura, S Hirohata, T Murakami, T Miyoshi, K Demircan, T Oohashi, H Ogawa, K Koten, K Toeda, S Kusachi, Y Ninomiya, Y Shiratori

    JOURNAL OF BIOCHEMISTRY   136 ( 4 )   439 - 446   2004.10

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    Extracellular matrix (ECM)-degrading enzymes such as matrix metalloproteases (MMPs) play an essential role in the repair of infarcted tissue, which affects ventricular remodeling after myocardial infarction. ADAMTS1 (A disintegrin and metalloprotease with thrombospondin motifs), a newly discovered metalloprotease, was originally cloned from a cancer cell line, but little is known about its contribution to disease. To test the hypothesis that ADAMTS1 appears in infarcted myocardial tissue, we examined ADAMTS1 mRNA expression in a rat myocardial infarction model by Northern blotting, real-time RT-PCR and in situ hybridization. Normal endothelium expressed little ADAMTS1 mRNA, while normal myocardium expressed no detectable ADAMTS1 mRNA. Up-regulation of ADAMTS1 was demonstrated by Northern blot analysis and real-time RT-PCR at 3 h after coronary artery ligation. In situ hybridization revealed strong ADAMTS1 mRNA signals in the endothelium and myocardium in the infarcted heart, mainly in the infarct zone, at 3 h after myocardial infarction. The rapid and transient up-regulation of the ADAMTS1 gene in the ischemic heart was distinct from the regulatory patterns of other MMPs. Our study demonstrated that the ADAMTS1 gene is a new early immediate gene expressed in the ischemic endothelium and myocardium.

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  • 新規ラットlink protein geneの同定と特性 Lp3/Hapln3(Identification and Characterization of a novel rat link protein gene: Lp3/Hapln3)

    小川 弘子, 廣畑 聡, 三好 亨, 村上 充, 白鳥 康史, 大橋 俊孝, 二宮 善文, 草地 省蔵, 佐田 政隆

    Circulation Journal   68 ( Suppl.III )   938 - 938   2004.10

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  • Combination of caspase transfer using the human telomerase reverse transcriptase promoter and conventional therapies for malignant glioma cells International journal

    H Takeuchi, T Kanzawa, Y Kondo, T Komata, S Hirohata, S Kyo, S Kondo

    INTERNATIONAL JOURNAL OF ONCOLOGY   25 ( 1 )   57 - 63   2004.7

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    Recently, we have reported the therapeutic efficacy of delivering initiator caspase (caspase-8) or executioner active caspase (rev-caspase-6) to telomerase-positive malignant glioma cells using the human telomerase reverse transcriptase (hTERT) gene promoter system (hTERT/caspase-8 or hTERT/rev-caspase-6). In the present study, we investigated if conventional treatments for malignant gliomas augment the efficacy of the hTERT/caspase therapy. First, we demonstrated that hTERT/rev-caspase-6 exhibited a greater ability to induce apoptosis in malignant glioma U87-MG and U373-MG cells than hTERT/caspase-8. Next, as conventional treatments to combine with hTERT/rev-caspase-6, apoptosis-inducing agents [cisplatin (CDDP), paclitaxel (PTX), and BCNU] and non-apoptosis-inducing therapies [temozolomide (TMZ) and gamma-irradiation (IR)] were used. Combination of hTERT/rev-caspase-6 gene therapy with PTX yielded a dose-dependent additive effect, while CDDP and BCNU had additive effect only when tumor cells were treated at IC75 of each agent. A decline in the combination effect of CDDP and BCNU at IC50 was due to decreased activity of telomerase in treated tumor cells prior to the hTERT/rev-caspase-6 transfer. On the other hand, TMZ or IR had no significant additive effect on induction of apoptosis. These results suggest that agents, which induce apoptosis without inhibiting telomerase activity are a promising counterpart to combine with hTERT/rev-caspase-6 therapy for the management of malignant gliomas.

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  • 新規マトリックスリンクプロテインLp3/Hapln3 クローニングおよびその発現解析

    小川 弘子, 廣畑 聡, 大橋 俊孝, 佐田 政隆, 村上 充, 二宮 善文, 草地 省蔵, 白鳥 康史, 大江 透

    日本動脈硬化学会総会プログラム・抄録集   36回   197 - 197   2004.7

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  • Spatially and temporally different expression of osteonectin and osteopontin in the infarct zone of experimentally induced myocardial infarction in rats

    Komatsubara, I, T Murakami, S Kusachi, K Nakamura, S Hirohata, J Hayashi, S Takemoto, C Suezawa, Y Ninomiya, Y Shiratori

    CARDIOVASCULAR PATHOLOGY   12 ( 4 )   186 - 194   2003.7

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    Osteonectin and osteopontin, two secreted matricellular proteins, have a variety of functions that are exerted through interaction with matrix components. These proteins appear in response to tissue injury. To test our hypothesis that osteopontin and osteonectin are expressed with spatially and temporally different patterns in myocardial infarct tissue, we investigated osteonectin and osteopontin expression in experimentally induced myocardial infarction in rats, in comparison with Type I collagen expression. Northern blotting demonstrated that osteonectin mRNA did not markedly increase on Day 2 after the infarction, but it increased on Days 7 and 14 by 1.7 +/- 0.12- and 1.8 +/- 0.01-fold compared to that in preligation hearts. In contrast, osteopontin mRNA was increased on Day 1 (41.9 +/- 11.3-fold increase) and on Day 2 (58.3 +/- 7.6-fold increase), and then it declined on Days 7 and 14 (24.8 +/- 9.0- and 13.5 +/- 4.7-fold increase, respectively). In situ hybridization revealed that osteonectin mRNA signals were observed in fibroblasts, myofibroblasts and macrophages around infarct necrotic tissue on Days 7 and 14. Osteopontin mRNA signals were observed in macrophages in the infarct marginal zone on Day 2. Immunopositive staining for both osteonectin and osteopontin showed the same pattern as that obtained by in situ hybridization. The time course of osteonectin mRNA was almost parallel with that of Type I collagen mRNA, while that of osteopontin was not. These results demonstrated spatially and temporally different expression patterns of osteonectin and osteopontin in myocardial infarction and suggest that osteonectin appears to be involved in the pathological course in the late phase after infarction concomitantly with Type I collagen, while osteopontin may play a role in the early phase. (C) 2003 Elsevier Inc. All rights reserved.

    DOI: 10.1016/S1054-8807(03)00042-5

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  • Osteogenic protein-1 reduces intercellular adhesion molecule-1 messenger RNA expression, infarct size and TUNEL-positive cardiomyocytes in ischemia/reperfusion rat hearts. Reviewed International journal

    Hayashi J, Kusachi S, Murakami T, Miyoshi T, Nakamura K, Koten K, Ogawa H, Hirohata S, Ninomiya Y, Shiratori Y

    Experimental and clinical cardiology   8 ( 4 )   195 - 200   2003

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    Background: Osteogenic protein, a member of the transforming growth factor-beta superfamily, has been reported to decrease the expression of intercellular adhesive molecules and prevent neutrophil accumulation and activity in tissue injury. Objective: To examine the effects of osteogenic protein on ischemia/reperfusion in rat hearts. Methods: Reperfusion was established after a 90 min ligation of the proximal left coronary artery in rats. Recombinant human osteogenic protein-1 (200 μg/kg) was administered via the femoral vein just before reperfusion. Intercellular adhesion molecule-1 (ICAM-1) messenger RNA (mRNA) expression and infarct size were evaluated using Northern blotting and triphenyl tetrazolium chloride staining, respectively. Terminal deoxynucleotidyl transferase mediated biotin-16-2′-deoxyuridine-5′-triphosphate nick end labeling (TUNEL) staining was also performed. Results: In osteogenic protein-1 treated rats, the expression of ICAM-1 mRNA in ischemia/reperfusion hearts rapidly increased 4 h after reperfusion, although, the increase was lower than that observed in the vehicle-treated hearts (7.4±1.6-old versus 14.6±3.7-fold increase compared to the increase observed in preligation control hearts, respectively). Similarly, in day 1 and day 7 hearts, the increase in ICAM-1 mRNA expression was significantly lower in ischemia/reperfusion hearts from rats treated with osteogenic protein-1 than in vehicle-treated rats (2.5±0.1-fold versus 5.8±2.3-fold and 1.5±0.3-fold versus 3.5±0.2-fold, respectively). Infarct size in rats treated with osteogenic protein-1 was significantly smaller than that observed in rats treated with vehicle (13.1±1.2% versus 28.5±5.7% of the left ventricle, P<0.01). The percentage of TUNEL-positive cardiomyocytes in ischemia/reperfusion hearts in rats treated with osteogenic protein-1 was significantly lower than in rats treated with vehicle (17.1±5.3% versus 31.1±4.5%, P< 0.01). Conclusion: The present study demonstrated that recombinant human osteogenic protein-1 suppressed ICAM-1 mRNA expression, reduced infarct size and decreased TUNEL-positive cardiomyocytes in ischemic/reperfused rat hearts. © 2003 Pulsus Group Inc. All rights reserved.

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  • 胆嚢炎に続発した感染性腹部大動脈瘤の一例

    三好亨, 広畑敦, 小天和也, 土井正行, 廣畑 聡, 瀬崎悟之, 村上充, 草地省蔵, 白鳥康史

    Circulation Journal   2003

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  • Intense response of heart rate with pronounced suppression of high-frequency power of heart rate variability to early morning exercise with high-intensity load Reviewed International journal

    J Ueta, T Nakatsu, T Murakami, S Toyonaga, S Hirohata, K Mashima, M Sangawa, S Kusachi, Y Shiratori

    BIOMEDICINE & PHARMACOTHERAPY   56 ( SUPPL. 2 )   353S - 358S   2002

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    Autonomic nerve activity shows circadian variation. Therefore, we put forward the hypothesis that the responses of heart rate (HR) and high-frequency (HF) power of HR variability to exercise would be different between-early morning and daytime exercise. We performed ergometer constant load exercise tests [50 watts (low), 100 watts (high load)] in the early morning and during the day in 6 healthy volunteers. The HR response was fitted to an exponential hyperbolic sine function: HR = alpha*e(-beta*t) *sinh(omega*t)+gamma. In this equation, the beta/omega ratio was inversely correlated with the intensity of the HR response. HF power was determined using a recently developed algorithm with high time-resolution power. There were no significant differences in HR, HF power or systolic blood pressure (BP) pressure before exercise between early morning and daytime exercise with either the 50 or 100 watt loads. During exercise, there were no significant differences in maximal HR or maximal systolic BP between early morning and daytime exercise with either 50 or 100 watt loads. For high-load exercise, the beta/omega ratio was significantly lower in early morning exercise (mean+/-SD, 0.945+/-0.02) than in daytime exercise (0.987+/-0.03). Similarly, for 100 watt exercise, HF power of HR variability was significantly lower in early morning exercise (0.94+/-0.52 msec[Hz(1/2)) than in daytime exercise (1.26+/-0.74 msec/Hz(1/2)). In conclusion, the present study demonstrated that a lower beta/omega ratio in the HR response was associated with lower HF power of HR variability in early morning high-load exercise compared to that in daytime exercise, indicating that the heart rate responded more intensely to early morning exercise than to daytime exercise with a high load due, at least partly, to pronounced suppression of parasympathetic nerve activity. (C) 2002 Editions scientifiques et medicales Elsevier SAS. All rights reserved.

    DOI: 10.1016/s0753-3322(02)00316-5

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  • A novel treatment of human malignant gliomas in vitro and in vivo: FADD gene transfer under the control of the human telomerase reverse transcriptase gene promoter

    T Komata, S Koga, S Hirohata, M Takakura, IM Germano, M Inoue, S Kyo, S Kondo, Y Kondo

    INTERNATIONAL JOURNAL OF ONCOLOGY   19 ( 5 )   1015 - 1020   2001.11

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    Telomerase activity has a close relationship with malignancies in many cell types and it is tightly regulated at the transcriptional level of human telomerase reverse transcriptase (hTERT). Utilizing the hTERT promoter, the authors developed a gene delivery system of Fas associated protein with death domain (FADD) (hTERT/FADD). FADD is a protein which plays an important role in the apoptotic pathway of Fas. Overexpression of FADD induces apoptosis in the cells regardless of Fas expression on the cell surface. We hypothesized that we might be able to restrict the expression of FADD in malignant glioma cells if we use the gene transfer system under the control of hTERT promoter. This study was designed to investigate whether the hTERT/FADD construct induces apoptosis effectively in malignant glioma cells while keeping normal cells intact. First, using the reverse transcription-polymerase chain reaction (RT-PCR) technique, we confirmed that hTERT mRNA was expressed in human malignant glioma cells (U373-MG, A172 and GB-1), but not in cultured astrocytes (TEN) or fibroblasts (MRC5). After transient transfection with the hTERT/FADD construct, a significant number of FADD-positive cells and apoptotic cells were detected in hTERT-positive malignant glioma cells. In contrast, hTERT-negative astrocytes and fibroblasts remained intact. Furthermore, subcutaneously implanted U373-MG tumors treated with the hTERT/FADD construct reduced in volume significantly C compared to the conrol treatment (p=0.0001). Gene transfer of FADD under the control of the hTERT promoter may be a novel and promising therapy to kill hTERT-positive malignant glioma cells while sparing normal brain cells lacking hTERT.

    DOI: 10.3892/ijo.19.5.1015

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  • Increased expression of biglycan mRNA in pressure-overloaded rat heart

    Y Ayada, S Kusachi, T Murakami, S Hirohata, S Takemoto, Komatsubara, I, J Hayashi, A Iwabu, Y Ninomiya, T Tsuji

    CLINICAL AND EXPERIMENTAL HYPERTENSION   23 ( 8 )   633 - 643   2001.11

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    Biglycan mRNA expression in rat myocardium after abdominal aortic banding with renal ischemia was examined. The Northern blot analysis demonstrated that expression of biglycan mRNA in the pressure-overloaded hearts on days 2, 7, 14 and 28 was 2.88 +/-0.89, 2.32 +/-0.49, 2.17 +/-0.57 and 1.81 +/-0.46-fold higher, respectively, than that in the sham-operated hearts. In situ hybridization showed an increased density of biglycan mRNA signal-positive cells in the pressure-overloaded hearts. The cells with positive signals were spindle-shaped mesenchymal cells in the myocardial interstitium. A marked increase in biglycan mRNA signal expression was also observed in endothelial cells and smooth muscle cells of the thickened myocardial capillary wall. These results demonstrated an increase in biglycan mRNA in the pressure-overloaded heart in mesenchymal cells in the myocardial interstitium, and in endothelial and smooth muscle cells of the capillaries, indicating that biglycan contributes to the ventricular and vascular remodeling in response to pressure overload.

    DOI: 10.1081/CEH-100107393

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  • ラット心筋梗塞モデルでの新生血管におけるオステオネクチンmRNAの発現の経時的変化の検討

    前田 弘子, 村上 充, 廣畑 聡, 中村 圭吾, 岩部 明弘, 綾田 陽子, 瀬崎 悟之, 竹本 俊二, 小松原 一正, 草地 省蔵

    Japanese Circulation Journal   65 ( Suppl.III )   807 - 807   2001.10

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  • ラット実験的心筋梗塞モデルにおけるトロンボスポンジン-1mRNA発現の経時的変化の検討

    中村 圭吾, 廣畑 聡, 岩部 明弘, 綾田 陽子, 前田 弘子, 竹本 俊二, 瀬崎 悟之, 小松原 一正, 十枝 健一, 村上 充

    マトリックス研究会大会   ( 48 )   70 - 70   2001.4

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  • Spatial changes of gelatinolytic activity in myocardial infarction in rats

    Takashi Murakami, Shozo Kusachi, Satoshi Hirohata, Chisato Suezawa, Syunji Takemoto, Satoshi Sezaki, Takao Tsuji, Yoshifumi Ninomiyal

    Keio Journal of Medicine   50   54 - 63   2001.1

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    DOI: 10.2302/kjm.50.supplement3_54

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  • 新しい細胞外マトリックス分解酵素ADAMTSファミリー

    廣畑 聡

    生化学   73,11,1333-1337   2001

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  • Chromosomal assignment of two ADAM genes, TACE (ADAM17) and MLTNB (ADAM19), to human chromosomes 2 and 5, respectively, and of Mltnb to mouse chromosome 11

    Satoshi Hirohata, Michael F. Seldin, Suneel S. Apte

    Genomics   Nov 15;54(1):178-9 ( 1 )   178 - 179   1998.11

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    DOI: 10.1006/geno.1998.5544

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Books

  • 平成18-19年度科学研究費補助金(基盤研究(B))研究成果報告書

    2008 

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  • 平成16-17年度科学研究費補助金(基盤研究(C))研究成果報告書

    2006 

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  • 平成16-17年度科学研究費補助金(基盤研究(B))研究成果報告書

    2006 

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  • 平成17年度文部科学省補助事業成果報告書 医療・福祉・健康関連ミクロものづくり共同研究事業 ナノバイオテクノロジーに基づく新しい標的医療の創造とその基盤研究

    2006 

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  • 平成15-16年度科学研究費補助金(基盤研究(B))研究成果報告書

    2005 

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  • 平成14-15年度科学研究費補助金(基盤研究B)成果報告書

    2004 

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  • 平成13-14年度科学研究費補助金(基盤研究B)成果報告書

    2003 

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  • Advancement of Life Science

    Roan AMVO Publishing Company, Taipei  2003 

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MISC

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Presentations

  • APP669切断酵素ADAMTS4の同定

    金子直樹, 横山雅シャラ, 池村健太郎, 松崎将也, Gabriel Opoku, 伊永章史, 関谷禎規, 岩本慎一, 廣畑聡, 田中耕一, 富田泰輔

    第41回日本認知症学会学術集会 

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    Event date: 2022.11.25 - 2022.11.27

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  • ELUCIDATION OF THE TEMPORAL AND SPATIAL MODE OF EXTRACELLULAR MATRIX REMODELING IN VENTRAL WALL DEVELOPMENT.

    Gabriel Opoku, Kentaro Ikemura, Ryosuke Ando, Airi Nakano, Ren Takashita, Saeko Hirabayashi, Miki Taga, Omer Faruk Hatipoglu, Junko Inagaki, Satoshi Hirohata

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    Event date: 2022.11.9 - 2022.11.11

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  • アルツハイマー病血漿バイオマーカー分子APP669-711の産生酵素ADAMTS4の同定

    横山 雅シャラ, 金子 直樹, 松崎 将也, 吉澤 遥太, Hiroki Naito, Akihito Korenaga, 関禎規, 池村健太郎, Gabriel Opoku, 廣畑聡, 岩本慎一, 田中耕一, 富田泰輔

    第27回 日本病態プロテアーゼ学会 

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    Event date: 2022.8.19 - 2022.8.20

    Language:Japanese  

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  • 細胞外基質分解酵素を標的とした変形性関節症の新たな治療候補化合物

    中野 愛梨, 岩本 結衣, 池村 健太郎, 安藤 亮典, オポク ガブリエル, 高下 蓮, 平林 沙江子, 多賀 実紀, 勝山 惠理, 廣畑 聡

    第16回日本臨床検査学教育学会学術大会  2022.8.18 

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    Event date: 2022.8.18 - 2022.8.19

    Language:Japanese   Presentation type:Oral presentation (general)  

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  • ADAMTS4 as an enzyme cleaving at APP669 site.

    Naoki Kaneko, Miyabishara Yokoyama, Masaya Matsuzaki, Kentaro Ikemura, Gabriel Opoku, Akihito Korenaga, Sadanori Sekiya, Shinichi Iwamoto, Satoshi Hirohata, Koichi Tanak, Taisuke Tomita

    AAIC2022 (Alzheimer's Association International Conference 2022)  2022 

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    Event date: 2022.7.31 - 2022.8.4

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  • Crucial Role of TRPV2 in the Development of Hypoxia-induced Pulmonary Hypertension.

    Nakamura K, Katanosaka Y, Akagi S, Saito Y, Miyoshi T, Yoshida M, Hirohata S, Ito H

    第85回日本循環器学会 学術集会 

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    Event date: 2022.3.11 - 2022.3.23

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  • Clinical Study about Blood Thiamin (Vitamin B1) Concentration and Its Acute Phase Fluctuation in Patients with Congestive Heart Failure.

    飯田 倫公, 髙石 篤志, 岸之上 隆雄, 森 久寿, 山地 達也, 谷本 匡史, 大西 伸彦, 廣畑 聡

    第85回日本循環器学会 学術集会 

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    Event date: 2022.3.11 - 2022.3.23

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  • Examination of the Relationship between Blood Carnitine Concentration and Clinical Course in Patients with Congestive Heart Failure.

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    Event date: 2022.3.10 - 2022.3.23

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  • The role of ADAMTS1 in mice embryo development

    Gabriel Opoku, Kentaro Ikemura, Ryosuke Ando, Airi Nakano, Shintaro Kodama, Ren Takagishi, Minori Uraki, Junko Inagaki, Satoshi Hirohata

    第94回日本生化学会大会  2021.11 

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    Event date: 2021.11.3 - 2021.11.5

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  • XO阻害薬フェブキソスタットによる抗酸化作用は肝臓・血管系を保護する

    柿本麻衣, 藤井 萌, 佐藤生弥, 山元修成, 本間宏基, 奥川友葉, 柴田桃里, 小松千尋, 廣畑 聡, 渡辺彰吾

    第53回日本動脈硬化学会学術集会  2021.10 

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    Event date: 2021.10.23 - 2021.10.24

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  • フルクトース負荷による尿酸上昇がNASHと動脈硬化に及ぼす影響

    藤井 萌, 柿本 麻衣, 山元 修成, 佐藤 生弥, 本間 宏基, 小松 千尋, 奥川 友葉, 柴田 桃里, 廣畑 聡, 渡辺 彰吾

    第53回日本動脈硬化学会学術集会  2021.10 

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    Event date: 2021.10.23 - 2021.10.24

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  • 関節を構成する細胞への細胞外分泌小胞取り込みの検討

    兒玉 慎太郎, 池村 健太郎, 安藤 亮典, 中野 愛梨, Opoku Gabriel, 高下 蓮, 浦木 美能理, 稲垣 純子, 古松 毅之, 廣畑 聡

    第8回日本細胞外小胞学会  2021.10 

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    Event date: 2021.10.18 - 2021.10.19

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  • 非アルコール性脂肪肝炎線維化におけるオステオポンチンの発現

    安藤亮典, 畑本早紀子, 中野愛梨, 池村健太郎, 兒玉慎太郎, オポク・ガブリエル, 山元修成, 稲垣純子, 今重之, ハティポール・オメル・ファルク, 渡辺彰吾, 廣畑 聡

    第53回日本結合組織学会 学術大会  2021.6 

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    Event date: 2021.6.26 - 2021.6.27

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  • Crucial Role of TRPV2 in the Development of Hypoxia-induced Pulmonary Hypertension

    2021.3 

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    Event date: 2021.3.26 - 2021.3.28

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  • The Westerizaton of Life Style and Atherosclerosis in Japan –The Balance of EPA and AA- International conference

    EAS congress  2018 

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    Event date: 2018.5.5 - 2018.5.8

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  • Supplementation of Omega-3 PUFAs could improve long term prognosis after PCI in patients without hyperlipidemia and diabetes. International conference

    EAS congress  2018 

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    Event date: 2018.5.5 - 2018.5.8

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  • Inflammatory cytokine-induced matrix degrading enzymes expression were attenuated by mechanical stress through transient receptor potential cation channel

    ConBio2017  2017 

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    Event date: 2017.12.6 - 2017.12.9

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  • Molecular and biochemical analysis of HYBID (HYaluronan-Binding protein Involved in hyaluronan Depolymerization) gene expression.

    Ohtsuki T, Yoshida H, Shinaoka A, Kumagishi-Shinaoka K, Cilek MZ, Hatipoglu OF, Inagaki J, Nishida K,Okada Y, Hirohata S.

    第30回日本軟骨代謝学会  2017 

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    Event date: 2017.3.3 - 2017.3.4

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:京都市  

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  • リンパ管内皮細胞に対するADAMTS1の作用とシグナル伝達

    稲垣 純子, 高橋 克之, 小川 弘子, Hatipoglu Omer F., Zeynel Cilek Mehmet, 小比賀 真就, 廣畑 聡, 二宮 善文

    第85回日本生化学会大会  2012 

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    Event date: 2012.12.14 - 2012.12.16

    Language:Japanese   Presentation type:Poster presentation  

    Venue:福岡  

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  • The inhibitory effect of an angiotensin II converting enzyme inhibitor on gelatinase activity in experimental abdominal aortic aneurysm

    Toru Miyoshi, Tomoko Yonezawa, Kazufumi Nakamura, Satoshi Hirohata, Yoshifumi Ninomiya, Hiroshi Ito

    第20回日本血管生物医学会  2012 

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    Event date: 2012.12.5 - 2012.12.7

    Language:English   Presentation type:Poster presentation  

    Venue:徳島  

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  • The tumor growth inhibitory effect of ADAMTS1 is accompanied by the inhibition of tumor angiogenesis International conference

    Satoshi Hirohata, Takashi Ohtsuki, Masanari Obika, Hiroko Ogawa, Junko Inagaki, Shozo Kusachi, Yoshifumi Ninomiya

    2012 Biennial Meeting of American Society for Matrix Biology  2012 

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    Event date: 2012.11.11 - 2012.11.14

    Language:English   Presentation type:Poster presentation  

    Venue:サンディエゴ  

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  • Cyclic tensile strain inhibits Interleukin-1β and Tumor Necrosis Factor-α induced aggrecanase in human chondrosarcoma cell line OUMS-27 by stretch-activated channels International conference

    Takashi Ohtsuki, Keiichiro Nishida, Satoshi Hirohata,Yoshifumi Ninomiya

    2012 Biennial Meeting of American Society for Matrix Biology  2012 

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    Event date: 2012.11.11 - 2012.11.14

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    Venue:サンディエゴ  

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  • ADAMTS1ノックアウトマウスの解析

    廣畑 聡 ハティポール・オメル・ファルク 楠絵理子 メフメット・ゼイネル・チレッキ 大月孝志 稲垣純子 草地省蔵 二宮善文

    第44回日本結合組織学会学術大会 第59回マトリックス研究会大会 合同学術集会  2012 

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    Event date: 2012.6.7 - 2012.6.8

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    Venue:東京  

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  • ヒアルロン酸(HA)分子量と関節軟骨保護効果の解析

    大月孝志 メフメット・ゼイネル・チレッキ ハティポール・オメル・ファルク 西田圭一郎 二宮善文 廣畑 聡

    第44回日本結合組織学会学術大会 第59回マトリックス研究会大会 合同学術集会  2012 

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    Event date: 2012.6.7 - 2012.6.8

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    Venue:東京  

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  • ADAMTS1 inhibits angiogenesis by inducing apoptosis specifically on endothelial cell

    小比賀真就、廣畑 聡、幡中邦彦、小川弘子、三好亨、伊藤浩、草地省蔵、二宮善文

    第76回日本循環器学会総会  2012 

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    Event date: 2012.3.15 - 2012.3.17

    Language:English   Presentation type:Oral presentation (general)  

    Venue:横浜  

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  • Impact of collagen gene deficiency on the intimal hyperplasia after angioplasty

    小川弘子、廣畑 聡、小比賀真就、幡中邦彦、伊藤浩、佐田正隆、草地省蔵

    第76回日本循環器学会総会  2012 

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    Event date: 2012.3.15 - 2012.3.17

    Language:English   Presentation type:Oral presentation (general)  

    Venue:横浜  

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  • Impact of fluorescent imaging with E-selectin-targeted liposome on non-invasie assessment of therapeutic effect for atherosclerosis in mice

    幡中邦彦、小川弘子、小比賀真就、伊藤浩、廣畑 聡

    第76回日本循環器学会総会  2012 

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    Event date: 2012.3.15 - 2012.3.17

    Language:English   Presentation type:Oral presentation (general)  

    Venue:横浜  

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  • ADAMTS1 plays a role in apoptosis by mediating TNF-α receptor1

    小比賀真就、廣畑 聡、幡中邦彦、小川弘子、三好亨、伊藤浩、草地省蔵、二宮善文

    第76回日本循環器学会総会  2012 

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    Event date: 2012.3.15 - 2012.3.17

    Language:English   Presentation type:Oral presentation (general)  

    Venue:横浜  

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  • メカニカルストレスとサイトカイン

    大月孝志、廣畑 聡、西田圭一郎、二宮善文

    第25回日本軟骨代謝学会  2012 

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    Event date: 2012.3.9 - 2012.3.10

    Language:Japanese   Presentation type:Poster presentation  

    Venue:名古屋  

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  • Hyaluronan inhibits aggrecanase in human chondrosarcoma cell line OUMS-27 in a size dependent manner

    Takashi Ohtsuki, Keiichiro Nishida, Satoshi Hirohata, Yoshifumi Ninomiya

    MBJ2011 第34回日本分子生物学会年会  2011 

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    Event date: 2011.12.13 - 2011.12.16

    Language:English   Presentation type:Poster presentation  

    Venue:横浜  

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  • 虚血性心疾患患者によるCAVIと冠動脈硬化、左心機能の関連性の検討

    小川弘子、三好亨、土井正行、廣畑 聡、草地省蔵、小出典男

    第58回日本臨床検査医学会学術集会  2011 

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    Event date: 2011.11.17 - 2011.11.20

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:岡山  

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  • 非糖尿病性未治療高血圧患者におけるUACRの分布とhigh-normalの頻度

    小川弘子、大丸奈月、中津高明、泉 礼司、間島圭一、土岐美沙子、小林亜紗子、廣畑 聡、池田 敏、草地省蔵

    第58回日本臨床検査医学会学術集会  2011 

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    Event date: 2011.11.17 - 2011.11.20

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:岡山  

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  • 急性冠症候群患者における血清ADAMTS1レベルの上昇

    廣畑 聡 小比賀真就 幡中邦彦 小川弘子 三好亨 石井裕子 坂本かおり 草地省蔵 伊藤浩 二宮善文

    第58回日本臨床検査医学会学術集会  2011 

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    Event date: 2011.11.17 - 2011.11.20

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:岡山  

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  • 発作性心房細動の出現率に対するarterial stiffness増加の影響

    小川弘子、三好亨、土井正行、廣畑 聡、草地省蔵、小出典男

    第58回日本臨床検査医学会学術集会  2011 

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    Event date: 2011.11.17 - 2011.11.20

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:岡山  

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  • ARB内服中高血圧患者に対するカルシウム拮抗薬もしくは利尿剤の追加がAugmentation indexへ与える影響

    三好亨、土井正行、小川弘子、廣畑 聡、草地省蔵、小出典男、伊藤浩

    第58回日本臨床検査医学会学術集会  2011 

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    Event date: 2011.11.17 - 2011.11.20

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:岡山  

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  • ADAMTS1 plays roles in endothelial cell apoptosis International conference

    Masanari Obika, Satoshi Hirohata, Omer Faruk Hatipoglu, Mehmet Zeynel Cilek, Hiroko Ogawa, Kunihiko Hatanaka, Toru Miyoshi, Shozo Kusachi, Yoshifumi Ninomiya

    アメリカ心臓協会(AHA) 学術集会  2011 

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    Event date: 2011.11.12 - 2011.11.16

    Language:English   Presentation type:Poster presentation  

    Venue:オーランド  

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  • ADAMTS1のin vitroでのリンパ管新生阻害効果

    稲垣純子、高橋克之、小川弘子、Omer F. Hatipoglu, M. Zeynel Cilek, 小比賀真就、米澤朋子、大橋俊孝、廣畑 聡、二宮善文

    第84回日本生化学会大会  2011 

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    Event date: 2011.9.21 - 2011.9.24

    Language:Japanese   Presentation type:Poster presentation  

    Venue:京都  

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  • ADAMTS1 is a novel acute biphasic marker for ischemia and reperfusion in myocardial infarction International conference

    S. Hirohata, H. Ogawa, T. Miyoshi, M. Obika, Y. Ninomiya, S. Kusachi, S. Usui, R. Shinohata, H. Ito

    欧州心臓学会議(ESC)  2011 

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    Event date: 2011.8.27 - 2011.8.31

    Language:English   Presentation type:Poster presentation  

    Venue:パリ  

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  • Attenuation of endothelial apoptosis induced by TNF-alpha in ADAMTS1 deficient cells International conference

    Satoshi Hirohata, Omer Faruk Hatipoglu, Mehmet Zeynel Cilek, Masanari Obika, Hiroko Ogawa, Shozo Kusachi, Yoshifumi Ninomiya

    ゴードンカンファレンス matrix metalloproteinase  2011 

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    Event date: 2011.8.7 - 2011.8.12

    Language:English   Presentation type:Poster presentation  

    Venue:アメリカ  

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  • Olmesartan Reduces Serum Adipocyte Fatty Acid-Binding Protein and Arterial Stiffness in Hypertensive Patients

    Toru Miyoshi, Kazufumi Nakamura, Hiroshi Morita, Satoshi Hirohata, Kunihisa Kohno, Satoshi Nagase, Masashi Yoshida, Norihisa Toh, Nobuhiro Nishii, Shozo Kusachi, Kengo Kusano, Hiroshi Itoh

    第75回日本循環器学会総会  2011 

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    Event date: 2011.8.3 - 2011.8.4

    Language:English   Presentation type:Oral presentation (general)  

    Venue:横浜  

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  • Hypertension and Aging are the Risk Factors to Lead AMI for Patients with a Favorable AA to EPA Balance

    Yasunori Arai, Masayuki Ueeda, Kenzo Kagawa, Hiroaki Otsuka, Satoko Ugawa, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Shozo Kusachi, Hiroshi Ito

    第75回日本循環器学会総会  2011 

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    Event date: 2011.8.3 - 2011.8.4

    Language:English   Presentation type:Oral presentation (general)  

    Venue:横浜  

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  • Plasma Adipocyte Fatty Acid-binding Protein is Associated with Chronic Kidney Disease and Coronary Lesion Severity in Type2 Diabetic Patients

    Masahito Kajiya, Toru Miyoshi, Masayuki Doi, Mutsumi Iwamoto, Kunio Nogami, Ko Takeda, Satoshi Hirohata, Shozo Kusachi, Hiroshi Itoh

    第75回日本循環器学会総会  2011 

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    Event date: 2011.8.3 - 2011.8.4

    Language:English   Presentation type:Oral presentation (general)  

    Venue:横浜  

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  • Impact of CD44 on the Development of Abdominal Aortic Aneurysm in Mice: the Interaction with Hyaluronic Acid and Macrophages

    Toru Miyoshi, Satoshi Hirohata, Shozo Kusachi, Kazufumi Nakamura, Hiroshi Morita, Kunihisa Kohno, Satoshi Nagase, Nobuhiro Nishii, Norihisa Toh, Masashi Yoshida, Kengo Kusano, Hiroshi Itoh

    第75回日本循環器学会総会  2011 

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    Event date: 2011.8.3 - 2011.8.4

    Language:English   Presentation type:Oral presentation (general)  

    Venue:横浜  

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  • The role of alpha556 chains of type IV collagen in restenosis after angioplasty

    Hiroko Ogawa, Tomoko Yonezawa, Masataka Sata, Satoshi Hirohata, Toshitaka Oohashi, Shozo Kusachi, Yoshifumi Ninomiya

    第43回日本動脈硬化学会学術集会  2011 

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    Event date: 2011.7.15 - 2011.7.16

    Language:English   Presentation type:Poster presentation  

    Venue:札幌  

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  • Endothelial cell-specific early immediate response gene expression in hypoxia

    Satoshi Hirohata Cilek Mehmet, Masanari Obika, Hiroko Ogawa, Hatipoglu Faruk, Toru Miyoshi, Shozo Kusachi, Yoshifumi Ninomiya

    第43回日本動脈硬化学会学術集会  2011 

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    Event date: 2011.7.15 - 2011.7.16

    Language:English   Presentation type:Poster presentation  

    Venue:札幌  

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  • A ratio of MDA-LDL to LDL-C represents plaque vulnerability in a patient with angina pectoris: VH-IVUS study

    Hiroaki Otsuka, Masayuki Ueeda, Kenzo Kagawa, Yasunori Arai, Satoko Ugawa, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Hiroshi Ito, Shozo Kusachi

    第43回日本動脈硬化学会学術集会  2011 

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    Event date: 2011.7.15 - 2011.7.16

    Language:English   Presentation type:Poster presentation  

    Venue:札幌  

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  • ADAMTS1は血管新生を阻害しアポトーシスを誘導する

    廣畑 聡 小比賀真就 オメル・ファルク・ハティポール 小川弘子 メフメット・ゼェイネル・チレッキ 稲垣純子 大月孝志 石井裕子 幡中邦彦 草地省蔵 米澤朋子 大橋俊孝 二宮善文

    第43回日本結合組織学会学術大会・第58回マトリックス研究会大会 合同学術集会  2011 

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    Event date: 2011.6.10 - 2011.6.11

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:大分  

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  • アンジオテンシンⅡ受容体拮抗薬(オルメサルタン)によるサイトカイン発現抑制効果と心機能保持効果

    大月孝志 篠畑綾子 廣畑 聡 草地省蔵 二宮善文

    第43回日本結合組織学会学術大会・第58回マトリックス研究会大会 合同学術集会  2011 

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    Event date: 2011.6.10 - 2011.6.11

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    Venue:大分  

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  • ADAMTS1は腫瘍壊死因子刺激下の内皮細胞におけるアポトーシスに関連する

    オメル・ファルク・ハティポール 小比賀真就 廣畑 聡 小川弘子 メフメット・ゼェイネル・チレッキ 稲垣純子 大月孝志 石井裕子 幡中邦彦 草地省蔵 米澤朋子 大橋俊孝 二宮善文

    第43回日本結合組織学会学術大会・第58回マトリックス研究会大会 合同学術集会  2011 

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    Event date: 2011.6.10 - 2011.6.11

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    Venue:大分  

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  • Altered Expression of Hypoxia Response in Ischemic Hind Limb in ADAMTS1 Hetero Mice International conference

    Mehmet Zeynel Cilek, Satoshi Hirohata, Hiroko Ogawa, Toru Miyoshi, Shozo Kusachi, Yoshifumi Ninomiya

    第5回高度医療都市を創出する未来技術国際シンポジウム  2011 

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    Event date: 2011.3.15

    Language:English   Presentation type:Poster presentation  

    Venue:岡山  

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  • ヒアルロン酸分子量とアグリカナーゼ発現抑制効果に関する検討

    大月孝志、廣畑 聡、西田圭一郎、二宮善文

    第24回日本軟骨代謝学会  2011 

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    Event date: 2011.3.4 - 2011.3.5

    Language:Japanese   Presentation type:Poster presentation  

    Venue:福岡  

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  • ADAMTS1 inhibit angiogenesis by inducing apoptosis in endothelial cells: in vitro and in vivo study International conference

    Masanari Obika, Satoshi Hirohata, Omer Faruk Hatipoglu, Mehmet Zeynel Cilek, Hiroko Ogawa, Toru Miyoshi, Shozo Kusachi, Yoshifumi Ninomiya

    第4回高度医療都市を創出する未来技術国際シンポジウム  2011 

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    Event date: 2011.2.8

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    Venue:岡山  

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  • ADAMTS1プロモーターは急性低酸素応答性に遺伝子を発現する

    Satoshi Hirohata, M. Zeynel Cilek, Omer F. Hatipoglu, Hiroko Ogawa, Toru Miyoshi, Masanari Obika, Ryoko Shinohata, Shozo Kusachi, Yoshifumi Ninomiya

    第8回がんとハイポキシア研究会  2011 

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    Event date: 2011.1.29 - 2011.1.30

    Language:Japanese   Presentation type:Poster presentation  

    Venue:札幌  

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  • 新規急性低酸素応答配列を用いた遺伝子発現ベクターによる急性低酸素下のレポーター遺伝子の発現様式

    オメル・ファルク・ハティポール,メフメット・ゼェイネル・チレッキ,廣畑 聡,小川 弘子,稲垣 純子,大月 孝志,熊岸 香苗,草地 省蔵,二宮 善文

    第33回日本分子生物学会年会 第83回日本生化学会大会合同大会  2010 

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    Event date: 2010.12.7 - 2010.12.10

    Language:English   Presentation type:Poster presentation  

    Venue:神戸市  

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  • ADAMTS1 induces apoptosis on endothelial cells International conference

    9th National Medical Congress of Turkish Medical Genetics Society  2010 

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    Event date: 2010.12.1 - 2010.12.5

    Language:English   Presentation type:Oral presentation (general)  

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  • ADAMTS1 gene transfer inhibits angiogenesis and tumor growth International conference

    9th National Medical Congress of Turkish Medical Genetics Society  2010 

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    Event date: 2010.12.1 - 2010.12.5

    Language:English   Presentation type:Oral presentation (invited, special)  

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  • Chronic Kidney Disease is a Strong Predictor Related to the Severity of Coronary Artery Lesion in Patients with Stable Angina Pectoris International conference

    Dan K, Ueeda M, Ohtsuka H, Ugawa S, Ohnishi N, Takaishi A, Hirohata S, Kusachi S, Kusano K, Ito H.

    アメリカ心臓協会(AHA) 学術集会  2010 

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    Event date: 2010.11.13 - 2010.11.17

    Language:English   Presentation type:Poster presentation  

    Venue:シカゴ  

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  • Serum Adipocyte Fatty Acid-Binding Protein is Associated With Coronary Lesion Complexity in Patients With Coronary Artery Disease International conference

    Doi M, Miyoshi T, Iwamoto M, Nogami K, Kajiya M, Takeda K, Hirohata S, Kusachi S, Ito H.

    アメリカ心臓協会(AHA) 学術集会  2010 

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    Event date: 2010.11.13 - 2010.11.17

    Language:English   Presentation type:Poster presentation  

    Venue:シカゴ  

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  • Cd44 Contributes to the Development of Abdominal Aortic Aneurysm in Mice Through the Interaction With Hyaluronic Acid and the Recruitment of Macrophages International conference

    Miyoshi T, Yonezawa T, Hirohata S, Nakamura K, Kusachi S, Kusano K, Ninomiya Y, Ito H.

    アメリカ心臓協会(AHA) 学術集会  2010 

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    Event date: 2010.11.13 - 2010.11.17

    Language:English   Presentation type:Poster presentation  

    Venue:シカゴ  

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  • 心筋芽細胞分化促進因子の心筋梗塞および活性酸素細胞障害に対する効果

    石井裕子 廣畑 聡、上川 滋、妹尾昌治、草地省蔵 米澤朋子 大橋俊孝 二宮善文

    第42回日本結合組織学会学術大会・第57回マトリックス研究会大会 合同学術集会  2010 

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    Event date: 2010.8.19 - 2010.8.20

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:秋田市  

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  • ADAMTS1プロモーターは急性低酸素状態の内皮細胞選択的に遺伝子発現を誘導する

    Mehmet Zeynel Cilek, 廣畑 聡 Omer F. Hatipoglu, 小川弘子 三好 亨 稲垣純子 大月孝志 大橋俊孝 米澤朋子 原田 浩、上川 滋、草地省蔵 二宮善文

    第42回日本結合組織学会学術大会・第57回マトリックス研究会大会 合同学術集会  2010 

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    Event date: 2010.8.19 - 2010.8.20

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    Venue:秋田市  

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  • ADAMTS1の内皮細胞に対するアポトーシス効果の検討

    Omer F. Hatipoglu, 廣畑 聡 小比賀真就 Mehmet Zeynel Cilek, 小川弘子 三好 亨 稲垣純子 大月孝志 草地省蔵 米澤朋子 大橋俊孝 二宮善文

    第42回日本結合組織学会学術大会・第57回マトリックス研究会大会 合同学術集会  2010 

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    Event date: 2010.8.19 - 2010.8.20

    Language:Japanese   Presentation type:Poster presentation  

    Venue:秋田市  

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  • ADAMTS1のin vitroでのリンパ管新生阻害効果

    稲垣純子 高橋克之 Omer F. Hatipoglu, Mehmet Zeynel Cilek, 小比賀真就 米澤朋子 大橋俊孝 廣畑 聡 二宮善文

    第42回日本結合組織学会学術大会・第57回マトリックス研究会大会 合同学術集会  2010 

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    Event date: 2010.8.19 - 2010.8.20

    Language:Japanese   Presentation type:Poster presentation  

    Venue:秋田市  

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  • ADAMTS1遺伝子治療はプロテアーゼ非依存的に血管新生阻害効果を発揮し、腫瘍増大を阻害する

    廣畑 聡 小比賀真就 Omer F. Hatipoglu, 小川弘子Mehmet Zeynel Cilek, 高橋克之 稲垣純子 三好 亨 大月孝志 石井裕子 草地省蔵 米澤朋子 大橋俊孝 二宮善文

    第42回日本結合組織学会学術大会・第57回マトリックス研究会大会 合同学術集会  2010 

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    Event date: 2010.8.19 - 2010.8.20

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:秋田市  

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  • アンジオテンシンⅡ受容体拮抗薬(オルメサルタン)による新負荷モデルラットのCTGF発現抑制効果

    大月孝志 廣畑 聡 岩本睦 篠畑綾子 草地省蔵 二宮善文

    第42回日本結合組織学会学術大会・第57回マトリックス研究会大会 合同学術集会  2010 

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    Event date: 2010.8.19 - 2010.8.20

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    Venue:秋田市  

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  • プロテアーゼ活性に依存しない血管内皮細胞への作用によりADAMTS1は腫瘍発育を阻害する

    廣畑 聡, 小比賀真就, オメル・ファルク・ハティポール, 小川弘子, メフメット・ゼェイネル・チレッキ, 高橋克之, 稲垣純子, 三好亨, 大月孝志, 石井裕子,草地省蔵,米澤朋子, 大橋俊孝, 二宮善文

    第7回日本病理学会カンファレンス  2010 

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    Event date: 2010.8.6 - 2010.8.7

    Language:Japanese   Presentation type:Poster presentation  

    Venue:岡山市  

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  • Ox-LDL (MDA-LDL) is strongly influenced by LDL/HDL-C ratio, and significantly higher in patients with ACS than SAP or normal coronary.

    Kagawa K, Ueeda M, Otsuka H, Ugawa S, Dan K, Ohnishi N, Takaishi A, Hirohata S, Kusachi S, Ito H

    第42回 日本動脈硬化学会・学術集会  2010 

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    Event date: 2010.7.15 - 2010.7.16

    Language:Japanese   Presentation type:Poster presentation  

    Venue:岐阜市  

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  • Estimated GFR and omega 6 to 3 PUFAs balance (AA/EPA) has no significant relationship to ox-LDL level in patients with coronary heart disease.

    Otsuka H, Ueeda M, Kagawa K, Ugawa S, Dan K, Ohnishi N, Takaishi A, Hirohata S, Kusachi S, Ito H

    第42回 日本動脈硬化学会・学術集会  2010 

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    Event date: 2010.7.15 - 2010.7.16

    Language:Japanese   Presentation type:Poster presentation  

    Venue:岐阜市  

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  • 好酸球カチオンタンパク質はH2O2刺激下H9C2細胞に保護的に働く

    石井裕子、廣畑 聡、上川 滋、妹尾昌治、草地省蔵、二宮善文

    第51回日本生化学会 中国四国支部例会  2010 

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    Event date: 2010.5.14 - 2010.5.15

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:山口市  

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  • ADAMTS1 is a Novel Biomarker for Acute ischemia/reperfusion in Myocardial infarction Patients

    廣畑 聡, 小比賀真就, オメル・ファルク・ハティポール, 小川弘子, メフメット・ゼェイネル・チレッキ, 高橋克之, 稲垣純子, 三好亨, 大月孝志, 石井裕子,草地省蔵,米澤朋子, 大橋俊孝, 二宮善文

    第73回日本循環器学会総会  2010 

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    Event date: 2010.3.5 - 2010.3.7

    Language:English   Presentation type:Poster presentation  

    Venue:福岡市  

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  • Distribution of Plaque-Targeting Fluorescent Accumulation were associated with condensed Vascular Formation from the Vasa Vasorum in Atherosclerotic Plaque

    Ogawa H, Hirohata S, Toru Miyoshi, Kamikawa S, Obika M, Kusachi S, Ninomiya Y

    第73回日本循環器学会総会  2010 

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    Event date: 2010.3.5 - 2010.3.7

    Language:English   Presentation type:Oral presentation (general)  

    Venue:福岡市  

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  • A Novel Cationic Protein Protected H9c2 Cells from Oxidative Stress Induced by H2O2 through Akt Signaling

    Kamikawa S, Hirohata S, Toru Miyoshi, Ogawa H, Obika M, Kusachi S, Itoh H, Seno M, Ninomiya Y

    第73回日本循環器学会総会  2010 

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    Event date: 2010.3.5 - 2010.3.7

    Language:Japanese   Presentation type:Poster presentation  

    Venue:福岡市  

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  • Sexual Difference of Risk Factors Related to Plaque Vulnerability: A Study with VH-IVUS

    Ohtsuka H, Ueeda M, Takaishi A, Ohnishi N, Dan K, Ugawa S, Kagawa K, Hirohata S, Kusachi S, Kusano K, Itoh H.

    第73回日本循環器学会総会  2010 

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    Event date: 2010.3.5 - 2010.3.7

    Language:Japanese   Presentation type:Poster presentation  

    Venue:福岡市  

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  • Increased Plasma Adipocyte Fatty Acid-binding Protein as a Risk of Coronary Artery Disease in Men

    Higashiya S, Miyoshi T, Doi M, Takeda K, Nogami K, Yumoto A, Iwamoto M, Hirohata S, Kusachi S, Itoh H

    第73回日本循環器学会総会  2010 

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    Event date: 2010.3.5 - 2010.3.7

    Language:Japanese   Presentation type:Poster presentation  

    Venue:福岡市  

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  • The role of CD44 in the Development of Experimental Abdominal Aortic Aneurysm

    Miyoshi T, Hirohata S, Kamikawa S, Ogawa H, Kusachi S, Itoh H, Ninomiya Y

    第73回日本循環器学会総会  2010 

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    Event date: 2010.3.5 - 2010.3.7

    Language:English   Presentation type:Poster presentation  

    Venue:福岡市  

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  • A Novel Cationic Protein Reduced Infracted Size and Protected Myocytes From Oxidative Stress Through Modification of Akt Signaling. International conference

    Kamikawa S, Hirohata S, Watanabe S, Ohtsuki T, Miyoshi T, Ogawa H, Kusachi S, Senoo M, Ninomiya Y, Itoh H.

    アメリカ心臓協会(AHA) 学術集会  2009 

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    Event date: 2009.11.14 - 2009.11.18

    Language:English   Presentation type:Poster presentation  

    Venue:ニューオリンズ  

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  • Association of Increased Plasma Adipocyte Fatty Acid-binding Protein With Coronary Artery Disease in Men. International conference

    Higashiya S, Doi M, Nogami K, Iwamoto M, Yumoto A, Takeda K, Ueeda M, Miyoshi T, Hirohata S, Kusachi S, Ninomiya Y, Itoh H

    アメリカ心臓協会(AHA) 学術集会  2009 

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    Event date: 2009.11.14 - 2009.11.18

    Language:English   Presentation type:Poster presentation  

    Venue:ニューオリンズ  

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  • ADAMTS-1 is an Endothelial Cell-specific Hypoxia-inducible Gene. International conference

    Hirohata S, Hatipoglu OF, Miyoshi T, Ogawa H, Obika M, Kamikawa S, Kusachi S, Itoh H, Ninomiya Y.

    アメリカ心臓協会(AHA) 学術集会  2009 

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    Event date: 2009.11.14 - 2009.11.18

    Language:English   Presentation type:Poster presentation  

    Venue:ニューオリンズ  

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  • HIF-1 directly induced ADAMTS1 mRNA expression in hypoxic endothelial cells. International conference

    Hirohata S, Hatipoglu OF, Cilek MZ, Demircan K, Ogawa H, Miyoshi T, Obika M, Shinohata R, Kusachi S, Ninomiya Y

    MMPゴードンカンファレンス  2009 

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    Event date: 2009.8.30 - 2009.9.4

    Presentation type:Poster presentation  

    Venue:Les Diablerets, Switzerland  

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  • Combination therapy of angiontensin II receptor blockers plus a calcium channel blocker, but not a diuretic, improve late systolic pressure augmentation index in elderly patients with essential hypertension International conference

    Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Shozo Kusachi、Kengo Kusano

    欧州心臓協会(ESC)年次集会  2009 

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    Event date: 2009.8.29 - 2009.9.2

    Language:English   Presentation type:Poster presentation  

    Venue:Barcelona, Spain  

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  • Atrial stiffness is an independent determinant of B-type natriuretic peptide in patients with paroxysmal atrial fibrillation International conference

    Masayuki Doi Toru Miyoshi, Hirohata Satoshi, Shozo Kusachi, Kengo Kusano

    欧州心臓協会(ESC)年次集会  2009 

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    Event date: 2009.8.29 - 2009.9.2

    Language:English   Presentation type:Poster presentation  

    Venue:Barcelona, Spain  

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  • The association of serum adipocyte fatty acid binding protein with coronary atherosclerotic burden measured by intravascular ultrasound International conference

    Toru Miyoshi、Atsushi Hirohata, Satoshi Hiroahta, Shozo Kusachi, Kengo Kusano

    欧州心臓協会(ESC)年次集会  2009 

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    Event date: 2009.8.29 - 2009.9.2

    Language:English   Presentation type:Oral presentation (general)  

    Venue:Barcelona, Spain  

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  • The ratio of n-6 to n-3 polysaturated fatty acids reflects vulnerability of coronary plaques: a study with a virtual histology intravascular ultrasound.

    Yoichi Takaya, Masayuki Ueeda, Yukari Nakano, Satoko Ugawa, Kazuhiro Dan, Takenori Domei, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Shozo Kusachi, Kengo Kusano

    第41回日本動脈硬化学会総会  2009 

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    Event date: 2009.7.17 - 2009.7.18

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

    Venue:下関市  

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  • Average age of acute myocardial infarction (AMI) began to decline due to increase of younger age AMI in our hospital.

    Nakano Y., Ueeda M., Ohnishi N., Dan K., Ugawa S., Takaishi A., Kagawa K., Takaya Y., Hirohata S., Kusachi S.

    第41回日本動脈硬化学会総会  2009 

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    Event date: 2009.7.17 - 2009.7.18

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:下関市  

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  • Angiosculpt is a unique and powerful ballooning device to score a highly calcified lesion and in-stent restenosis.

    CVIT2009  2009 

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    Event date: 2009.6.25 - 2009.6.27

    Language:Japanese   Presentation type:Oral presentation (general)  

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  • The effect of olmesartan, an angiotensin II receptor blocker on the relationship between adiponectin and arterial stiffness in hypertensive patients with high body mass index International conference

    19th European Meeting on Hypertension  2009 

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    Event date: 2009.6.12 - 2009.6.16

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  • Beneficial effect of combination treatment with angiotensin II receptor blockers plus a calcium channel blocker on augmentation index in elderly patients with essential hypertension International conference

    19th European Meeting on Hypertension  2009 

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    Event date: 2009.6.12 - 2009.6.16

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  • Eosinophil Cationic Protein (ECP) Protects hearts against myocardial infarction International conference

    PPCTSS (PanPacific Connective Tissue Society Symposium)  2009 

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    Event date: 2009.6.4 - 2009.6.7

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  • ADAMTS1 as a hypoxia sensing biomarker International conference

    PPCTSS (PanPacific Connective Tissue Society Symposium)  2009 

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    Event date: 2009.6.4 - 2009.6.7

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  • ADAMTS1 is induced by hypoxia in endothelial cells and HIF-1 binds to the ADAMTS1 promoter International conference

    PPCTSS (PanPacific Connective Tissue Society Symposium)  2009 

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    Event date: 2009.6.4 - 2009.6.7

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  • Gene transfer of ADAMTS1 induced apoptosis in endothelial cells and inhibited tumor growth International conference

    PPCTSS (PanPacific Connective Tissue Society Symposium)  2009 

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    Event date: 2009.6.4 - 2009.6.7

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

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  • The 3’-untranslated Region of ADAMTS1 Regulates Its Expression International conference

    The 3rd International Congress of Molecular Medicine  2009 

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    Event date: 2009.5.5 - 2009.5.8

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  • Utilization of ADAMTS1 as A New Tool For Detecting Hypoxia International conference

    The 3rd International Congress of Molecular Medicine  2009 

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    Event date: 2009.5.5 - 2009.5.8

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  • Identification of NF-κB binding elements in human ADAMTS9 promoter International conference

    The 3rd International Congress of Molecular Medicine  2009 

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    Event date: 2009.5.5 - 2009.5.8

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  • In vivo imaging of Atherosclerosis with Targeting Liposome and its availability as a Drug Delivery System International conference

    The 10th International Cell Transplant Congress  2009 

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    Event date: 2009.4.20 - 2009.4.21

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  • HIF-1 Directly Induced Novel Metalloproteinase ADAMTS1 Expression and ADAMTS1 under Hypoxia Accelerated Endothelial Cell Migration

    Satoshi Hirohata, Hiroko Ogawa, Toru Miyoshi, Shigeshi Kamikawa, Kunihiko Hatanaka, Masanari Obika, Shozo Kusachi, Kengo Kusano

    第73回日本循環器学会総会  2009 

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    Event date: 2009.3.20 - 2009.3.22

    Language:English   Presentation type:Poster presentation  

    Venue:大阪市  

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  • Olmesartan Decreased Serum TGF-β Level and Protected Fibrotic Change in Rat Pressure Overload Heart

    Mutsumi Iwamoto, Satoshi Hirohata, Toru Miyoshi, Hiroko Ogawa, Masanari Obika, Hitoshi Yamawaki, Shozo Kusachi, Kengo Kusano

    第73回日本循環器学会総会  2009 

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    Event date: 2009.3.20 - 2009.3.22

    Language:English   Presentation type:Poster presentation  

    Venue:大阪市  

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  • Difference of Risk Factors and PUFAs between Generations and Sex in Patients of Acute Myocardinal Infarction

    Satoko Ugawa, Masayuki Ueeda, Yukari Nakano, Kazuhiro Dan, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Shozo Kusachi

    第73回日本循環器学会総会  2009 

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    Event date: 2009.3.20 - 2009.3.22

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    Venue:大阪市  

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  • Heart Rate Circadian Rhythm is the Strongest Factor to Determine the BNP Level in Permanent AF without LV Systolic Dysfunction

    Shigeshi Kamikawa, Yoko Kaji, Kosuke Sakane, Toru Miyoshi, Satoshi Hirohata, Shozo Kusachi, Masayuki Doi.

    第73回日本循環器学会総会  2009 

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    Event date: 2009.3.20 - 2009.3.22

    Language:English   Presentation type:Poster presentation  

    Venue:大阪市  

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  • Differential Effects of Calcium Channel Blocker and Diuretic in Combination with Angiotensin II Receptor Blockers on Late Systolic Pressure Augmentation

    Toru Miyoshi, Masayuki Doi, Satoshi Hirohata, Yoko Kaji, Kosuke Sakane, Shigeshi Kamikawa, Hiroko Ogawa, Shozo Kusachi, Kengo Kusano

    第73回日本循環器学会総会  2009 

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    Event date: 2009.3.20 - 2009.3.22

    Language:English   Presentation type:Poster presentation  

    Venue:大阪市  

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  • A Novel Drug Delivery System with Targeting Liposome Reduced Inflammation in Macrophages

    Hiroko Ogawa, Satoshi Hirohata, Kunihiko Hatanaka, Toru Miyoshi, Shigeshi Kamikawa, Mutsumi Iwamoto, Shozo Kusachi, Kengo Kusano

    第73回日本循環器学会総会  2009 

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    Event date: 2009.3.20 - 2009.3.22

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:大阪市  

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  • Significant Increase of Cholesterol, Trigriceride and AA were Observed in AMI; From 20 Years Database in Mitoyo General Hospital

    Yukari Nakano, Masayuki Ueeda, Satoko Ugawa, Kazuhiro Dan, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Shozo Kusachi.

    第73回日本循環器学会総会  2009 

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    Event date: 2009.3.20 - 2009.3.22

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    Venue:大阪市  

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  • Relationship between Adipocyte Fatty Acid-Binding Protein and Coronary Plaque Burden - An Intravascular Ultrasound Study.

    Go Onoue, Toru Miyoshi, Atsushi Hirohata, Satoshi Hirohata, Hiroko Ogawa, Shigeshi Kamikawa, Shozo Kusachi, Kengo Kusano.

    第73回日本循環器学会総会  2009 

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    Event date: 2009.3.20 - 2009.3.22

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    Venue:大阪市  

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  • QT Prolongation and Global ST-T Change are the Characteristics of Electrocardiogram of Heat Stroke

    Yukari Nakano, Masayuki Ueeda, Satoko Ugawa, Kazuhiro Dan, Nobuhiko Ohnishi, Atsushi Takaishi, Satoshi Hirohata, Shozo Kusachi.

    第73回日本循環器学会総会  2009 

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    Event date: 2009.3.20 - 2009.3.22

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    Venue:大阪市  

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  • Two Hyaluronan Receptors, Toll-like receptor-4 (TLR4) and CD44, Play Distinct Roles in Cytokine Induction in Monocytes

    Hitoshi Yamawaki, Satoshi Hirohata, Toru Miyoshi, Shigeshi Kamikawa, Hiroko Ogawa, Masanari Obika, Mutsumi Iwamoto, Kunihiko Hatanaka, Shozo Kusachi.

    第73回日本循環器学会総会  2009 

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    Event date: 2009.3.20 - 2009.3.22

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:大阪市  

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  • 低分子ヒアルロン酸によるサイトカイン誘導とヒアルロン酸レセプター

    高橋克之、○廣畑 聡、山脇 均、三好 亨、小川弘子、二宮善文

    第22回日本軟骨代謝学会  2009 

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    Event date: 2009.3.6 - 2009.3.7

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

    Venue:名古屋市  

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  • OUMS-27軟骨肉腫細胞または軟骨細胞におけるNFATc1を解したIL-1bによるADAMTS9遺伝子の活性化

    Kursat Oguz Yaykasli, Toshitaka Oohashi, Satoshi Hirohata, Omer Faruk Hatipoglu, Kiichi Inagawa, Kadir Demircan, Yoshifumi Ninomiya

    第22回日本軟骨代謝学会  2009 

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    Event date: 2009.3.6 - 2009.3.7

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:名古屋市  

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  • The Inhibiton of the ADAMTS9 induced by Interleukin 1β using 11R-VIVIT peptide in OUMS-27 Chondrosarcoma Cells and in Human Chondrocytes International conference

    Kursat Oguz Yaykasli, Toshitaka Oohashi, Satoshi Hirohata, Omer Faruk Hatipoglu, Kiichi Inagawa, Kadir Demircan, Yoshifumi Ninomiya

    アメリカマトリックス研究会学術集会  2008 

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    Event date: 2008.12.7 - 2008.12.10

    Language:English   Presentation type:Poster presentation  

    Venue:サンディエゴ  

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  • CAVIは左室拡張障害の指標となるか?

    三好 亨、*廣畑 聡、土井正行、坂根弘祐、上川 滋、加地容子、北脇知己、草地省蔵

    第5回血管バイオメカニクス研究会  2008 

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    Event date: 2008.11.15

    Presentation type:Oral presentation (general)  

    Venue:東京  

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  • The Impact of Increased Augmentation Index of Radial Pressure Waveform on Paroxysmal Atrial Fibrillation International conference

    Youko Kaji, Toru Miyoshi, Masayuki Doi, *Satoshi Hirohata, Tadahisa Uesugi, Shigeshi Kamikawa, Kosuke Sakane, Shozo Kusachi, Kengo F. Kusano

    アメリカ心臓協会(AHA) 学術集会  2008 

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    Event date: 2008.11.8 - 2008.11.12

    Presentation type:Poster presentation  

    Venue:ニューオリンズ  

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  • Serum Adipocyte Fatty Acid-Binding Protein Levels are Independently Associated with Coronary Atherosclerosis International conference

    Toru Miyoshi, Atsushi Hirohata, Shinichi Usui, Keizo Yamamoto, Kazuyoshi Hina, *Satoshi Hirohata, Shozo Kusachi, Yoshifumi Ninomiya, Kengo F. Kusano

    アメリカ心臓協会(AHA) 学術集会  2008 

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    Event date: 2008.11.8 - 2008.11.12

    Presentation type:Poster presentation  

    Venue:ニューオリンズ  

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  • 高血圧患者へのオルメサルタン投与によるアディポサイトカインへの影響

    土井正行、三好亨、*廣畑 聡、草地省蔵

    第31回日本高血圧学会総会  2008 

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    Event date: 2008.10.9 - 2008.10.11

    Presentation type:Poster presentation  

    Venue:札幌  

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  • 高血圧患者における発作性心房細動とAugmentation Indexの増加との関係

    加地容子、三好亨、土井正行、*廣畑 聡、草地省蔵

    第31回日本高血圧学会総会  2008 

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    Event date: 2008.10.9 - 2008.10.11

    Presentation type:Poster presentation  

    Venue:札幌  

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  • Association between serum adipocyte fatty acid-binding protein and the extent of coronary atherosclerosis International conference

    Toru Miyoshi, Atsushi Hirohata, Shinichi Usui, Keizo Yamamoto, Kazuyoshi Hina, *Satoshi Hirohata, Shozo Kusachi, Yoshifumi Ninomiya, Kengo Kusano

    第6回アジア動脈硬化学会  2008 

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    Event date: 2008.9.25 - 2008.9.28

    Presentation type:Poster presentation  

    Venue:香港  

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  • 発作性心房細動患者におけるBNP上昇と橈骨動脈AIとの増加の関係

    加地容子、三好 亨、土井正行、*廣畑 聡、坂根弘祐、草地省蔵、大江 透

    第40回日本動脈硬化学会総会  2008 

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    Event date: 2008.7.10 - 2008.7.11

    Presentation type:Poster presentation  

    Venue:つくば  

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  • 冠動脈疾患患者におけるCardio-ankle vascular index (CAVI)と腎機能低下の関連

    坂根弘祐、三好 亨、土井正行、*廣畑 聡、加地容子、草地省蔵

    第40回日本動脈硬化学会総会  2008 

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    Event date: 2008.7.10 - 2008.7.11

    Presentation type:Poster presentation  

    Venue:つくば  

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  • Increased augmentation index of radial pulse wave in patients with paroxysmal atrial fibrillation International conference

    Toru Miyoshi, Masayuki Doi, Youko Kaji, *Satoshi Hirohata, Shigeshi Kamikawa, Shiozo Kusachi, Tohru Ohe

    アメリカ心臓学会(ACC) 学術集会  2008 

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    Event date: 2008.3.29 - 2008.4.1

    Presentation type:Poster presentation  

    Venue:シカゴ  

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  • In vivo Imaging of Atherosclerosis with Novel Targeting Liposomes

    Kunihiko Hatanaka, *Satoshi Hirohata, Hiroko Ogawa, Toru Miyoshi, Shigeshi Kamikawa, Mutsumi Iwamoto, Shozo Kusachi, Tohru Ohe

    第72回日本循環器学会総会  2008 

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    Event date: 2008.3.28 - 2008.3.30

    Presentation type:Oral presentation (general)  

    Venue:福岡  

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  • siRNA silencing reveals the role of vascular cell adhesion molecule-1 in vascular smooth muscle cell migration

    Toru Miyoshi, *Satoshi Hirohata, Kunihiko Hatanaka , Mutsumi Iwamoto, Hiroko Ogawa, Shigeshi Kamikawa, Shozo Kusachi, Tohru Ohe

    第72回日本循環器学会総会  2008 

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    Event date: 2008.3.28 - 2008.3.30

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    Venue:福岡  

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  • Unique Three-dimensional Construction of Neovessel Formation by Fluvastatin Treatment in the Infarcted Myocardium.

    Hiroko Ogawa, *Satoshi Hirohata, Masahiko Maruyama, Toru Miyoshi, Hitoshi Yamawaki, Mutsumi Iwamoto, Shigeshi Kamikawa, Kunihiko Hatanaka, Shozo Kusachi, Tohru Ohe

    第72回日本循環器学会総会  2008 

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    Event date: 2008.3.28 - 2008.3.30

    Presentation type:Poster presentation  

    Venue:福岡  

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  • Activin A as a Novel Marker of Infarct Size in Patients with Acute Myocardial Infarction Who Undergo Percutaneous Coronary Intervention

    Toru Miyoshi, *Satoshi Hirohata, Kunihiko Hatanaka , Mutsumi Iwamoto, Hiroko Ogawa, Shigeshi Kamikawa, Shozo Kusachi, Tohru Ohe

    第72回日本循環器学会総会  2008 

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    Event date: 2008.3.28 - 2008.3.30

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    Venue:福岡  

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  • Cardiac Myoblast Differentiation Promoting Factor Reduced Infarct Size and Preserved Cardiac Function in Rat Myocardial Infarction Model.

    Shigeshi Kamikawa, *Satoshi Hirohata, Masahiko Maruyama, Hiroko Ogawa, Toru Miyoshi, Hitoshi Yamawaki, Mutsumi Iwamoto, Kunihiko Hatanaka, Shozo Kusachi, Tohru Ohe

    第72回日本循環器学会総会  2008 

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    Event date: 2008.3.28 - 2008.3.30

    Presentation type:Oral presentation (general)  

    Venue:福岡  

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  • Complexity of differential response to hyaluronan stimulation of hyaluronan-receptors in human peripheral blood mononuclear cells

    *廣畑 聡、山脇均、三好亨、小川弘子、草地省蔵、大江透、二宮善文

    第30回日本分子生物学会年会・第80回日本生化学会大会 合同大会  2007 

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    Event date: 2007.12.11 - 2007.12.15

    Presentation type:Poster presentation  

    Venue:横浜  

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  • Serum Activin A Level Is Associated With Infarct Size In Patients With Acute Myocardial Infarction Who Undergo Successful Primary Percutaneous Coronary Intervention

    Toru Miyoshi, *Satoshi Hirohata, Tadahisa Uesugi, Minoru Hirota, Hiromichi Ohnishi, Kunio Nogami, Shozo Kusachi, Tohru Ohe

    アメリカ心臓協会 学術集会  2007 

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    Event date: 2007.11.4 - 2007.11.7

    Presentation type:Poster presentation  

    Venue:Orlando, Florida, USA  

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  • ピタバスタチンの脂質低下作用と動脈効果改善作用―多施設臨床試験による検討

    富永洋功、岩部明弘、末丸俊二、草地省蔵、大江 透、*廣畑 聡、十河泰司、武田 光、中津高明、松浦和義

    第39回日本動脈硬化学会総会  2007 

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    Event date: 2007.7.13 - 2007.7.14

    Presentation type:Poster presentation  

    Venue:大阪  

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  • 非侵襲的な動脈硬化指標CAVI(Cardio-ankle vascular index)は心臓超音波 検査における左室拡張能の指標と関連するか?

    三好 亨、土井正行、*廣畑 聡、上川 滋、加地 容子、草地 省蔵

    第39回日本動脈硬化学会総会  2007 

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    Event date: 2007.7.13 - 2007.7.14

    Presentation type:Poster presentation  

    Venue:大阪  

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  • ADAMTS/aggrecanases are differentially regulated following spinal cord injury International conference

    Kadir Demircan, *Satoshi Hirohata, Tomoyuki Takigawa, Tomoko Yonezawa, Masae Kurosaki, Keiichiro Nishida, Yoshifumi Ninomiya

    MMPゴードンカンファレンス  2007 

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    Event date: 2007.6.3 - 2007.6.8

    Presentation type:Poster presentation  

    Venue:Balga, Italy  

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  • ADAMTS1 is hypoxia inducible gene in endothelial cells International conference

    Omer Faruk Hatipoglu, *Satoshi Hirohata, Kadir Demircan, Yoshifumi Ninomiya

    MMPゴードンカンファレンス  2007 

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    Event date: 2007.6.3 - 2007.6.8

    Presentation type:Poster presentation  

    Venue:Balga, Italy  

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  • Versicanolysis was accelerated in the border zone of myocardial infarction International conference

    *Satoshi Hirohata, Ayako Takeuchi, Hiroko Ogawa, Kadir Demircan, Yoshifumi Ninomiya

    MMPゴードンカンファレンス  2007 

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    Event date: 2007.6.3 - 2007.6.8

    Presentation type:Poster presentation  

    Venue:Balga, Italy  

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  • Differential Expression of ADAMTS1 gene in cancer cell lines

    M. Zeynel Cilek, *Satoshi Hirohata, Kadir Demircan, Omer Faruk Hatipoglu, Hiroko Ogawa, Tomoko Yonezawa, Shozo Kusachi, Toshitaka Oohashi, Yoshifumi Ninomiya

    第39回日本結合組織学会学術大会・第54回マトリックス研究会大会 合同学術集会  2007 

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    Event date: 2007.5.9 - 2007.5.11

    Presentation type:Poster presentation  

    Venue:東京  

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  • ADAMTS-aggrecanases are differentially expressed in cultured astrocyte

    Kadir Demircan, *Satoshi Hirohata, Tomoko Yonezawa, Tomoyuki Takigawa, Masae Kurosaki, Keiichiro Nishida, Yoshifumi Ninomiya

    第39回日本結合組織学会学術大会・第54回マトリックス研究会大会 合同学術集会  2007 

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    Event date: 2007.5.9 - 2007.5.11

    Presentation type:Poster presentation  

    Venue:東京  

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  • Endothelium-specific inhibition of cell migration and proliferation by ADAMTS1

    *Satoshi Hirohata, Masanari Obika, Hiroko Ogawa, Toru Miyoshi, Mehmet Zeynel Cilek, Kadir Demircan, Omer Faruk Hatipoglu, Shozo Kusachi, Yoshifumi Ninomiya

    第39回日本結合組織学会学術大会・第54回マトリックス研究会大会 合同学術集会  2007 

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    Event date: 2007.5.9 - 2007.5.11

    Presentation type:Poster presentation  

    Venue:東京  

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  • CELLULAR MECHANISM FOR CYTOKINE INDUCTIONS IN HYALURONAN-STIMULATED HUMAN MONONUCLEAR CELLS International conference

    *Hirohata, S., Yamawaki, H., Miyoshi, T., Ogawa, H., Obika, M., Hatanaka, K., Kusachi, S., Yonezawa, T., Oohashi, T., Ninomiya, Y

    ヒアルロン酸サミッ  2007 

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    Event date: 2007.4.22 - 2007.4.27

    Presentation type:Poster presentation  

    Venue:Charleston, SC, USA  

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  • Differential LDL-oxidation by endothelial cells in mouse strains with different atherosclerosis susceptibility

    Toru Miyoshi, Satoshi Hirohata, Shozo Kusachi, Kengo Kusano, Toru Ohe

    第71回日本循環器学会総会  2007 

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    Event date: 2007.3.15 - 2007.3.17

    Presentation type:Oral presentation (general)  

    Venue:神戸  

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  • Tolerance and Diagnostic Accuracy of Adenosine Infusion for Myocardial Perfusion SPECT in a Japanese Population

    Kunihiko Hatanaka, Masayuki Doi, *Satoshi Hirohata, Shigeshi Kamikawa, Yoko Kaji, Hitoshi Yamawaki, Masanari Obika, Hiroko Ogawa, Mutsumi Iwamoto, Shozo Kusachi, Toru Ohe

    第71回日本循環器学会総会  2007 

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    Event date: 2007.3.15 - 2007.3.17

    Presentation type:Poster presentation  

    Venue:神戸  

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  • ADAMTS1 Inhibits Angiogenesis via Metalloprotease-independent Endothelium-specific Activity

    Masanari Obika, *Satoshi Hirohata, Hiroko Ogawa, Toru Miyoshi, Hitoshi Yamawaki, Shozo Kusachi, Toru Ohe

    第71回日本循環器学会総会  2007 

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    Event date: 2007.3.15 - 2007.3.17

    Presentation type:Oral presentation (general)  

    Venue:神戸  

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  • Frequency of Early Repolarization in Electrocardiogram in Chronic Hemodialys is Patients and its Clinical Characteristics

    Minoru Hirota, Kunio Nogami, Tadahisa Uesugi, Hiromichi Ohnishi, Ko Takeda, Noriko Okada, Akihiro Iwabu, Shozo Kusachi, *Satoshi Hirohata

    第71回日本循環器学会総会  2007 

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    Event date: 2007.3.15 - 2007.3.17

    Presentation type:Poster presentation  

    Venue:神戸  

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  • Olmesartan Attenuated Connective Tissue Growth Factor (CTGF) Expression in Vascular Smooth Muscle Cells and Ameliorated Cardiac Hypertrophy in Pressure-overload Rats

    Mutsumi Iwamoto, *Satoshi Hirohata, Masahiko Maruyama, Masanari Obika, Hitoshi Yamawaki, Hiroko Ogawa, Kunihiko Hatanaka, Toru Miyoshi, Shozo Kusachi, Toru Ohe

    第71回日本循環器学会総会  2007 

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    Event date: 2007.3.15 - 2007.3.17

    Presentation type:Poster presentation  

    Venue:神戸  

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  • Expression of ADAMTS9 gene in chondrocytes and its regulation

    *Satoshi Hirohata, Kadir Demircan, Keiichiro Nishida and Yoshifumi Ninomiya

    第20回日本軟骨代謝学会  2007 

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    Event date: 2007.3.2 - 2007.3.3

    Presentation type:Oral presentation (general)  

    Venue:岡山  

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  • ADAMTSプロテアーゼのうちADAMTS-4が心筋梗塞早期に誘導され、梗塞辺縁部でバーシカンを分解する

    *廣畑 聡、丸山昌彦、岩本 睦、カディール・デミルジャン、小川弘子、大橋俊孝、草地省蔵、二宮善文

    日本分子生物学会 2006 フォーラム  2006 

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    Event date: 2006.12.6 - 2006.12.8

    Venue:名古屋市  

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  • 内皮細胞特異的に作用するADAMTSプロテアーゼ由来新規ドメインの機能解析

    *廣畑 聡、小比賀真就、小川弘子、三好 亨、ファルク・ハティポール、草地省蔵、二宮善文.

    日本分子生物学会 2006 フォーラム  2006 

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    Event date: 2006.12.6 - 2006.12.8

    Venue:名古屋市  

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  • 動脈硬化感受性の異なるマウス系統間における血管平滑筋の酸化LDLに対する反応

    三好 亨、*廣畑 聡、草地 省蔵、草野 研吾、大江 透、Weibin Shi

    第89回日本循環器学会中国地方会  2006 

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    Event date: 2006.11.25

    Venue:宇部市  

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  • Decreased serum levels of interferon gamma inducible protein 10 (IP-10) in acute myocardial infarction patients after successful primary percutaneous coronary intervention are associated with a smaller infarct size

    *Satoshi Hirohata, Kazuya Koten, Shinichi Usui, Hiroko Ogawa, Hitoshi Yamawaki, Masanari Obika, Mutsumi Iwamoto, Yasushi Shiratori, Shozo Kusachi, Tohru Ohe

    アメリカ心臓病協会(AHA)年次集会  2006 

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    Event date: 2006.11.12 - 2006.11.15

    Venue:シカゴ  

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  • Statin treatment accelerated neovessel formation in the border zone of the infarcted heart: Architectural study by vascular corrosion casting method using scanning electron microscopy.

    Mutsumi Iwamoto, *Satoshi Hirohata, Masahiko Maruyama, Kunihiko Hatanaka, Hiroko Ogawa, Yasushi Shiratori

    アメリカ心臓病協会(AHA)年次集会  2006 

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    Event date: 2006.11.12 - 2006.11.15

    Venue:シカゴ  

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  • Tolerance and diagnostic accuracy of an adenosine infusion for myocardial scintigraphy in Japanese

    Kunihiko Hatanaka, Masayuki Doi, Shigeshi Kamikawa, Yoko Kaji, Hitoshi Yamawaki, Mutsumi Iwamoto, *Satoshi Hirohata, Yasushi Shiratori.

    ヨーロッパ核医学協会2006年次集会  2006 

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    Event date: 2006.9.30 - 2006.10.4

    Venue:アテネ市  

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  • ヒト末梢血単球成分におけるヒアルロン酸の炎症反応誘導機構の解析

    山脇 均、*廣畑 聡、小川弘子、二宮善文、草地省蔵、白鳥康史、大江 透

    第37回日本動脈硬化学会総会  2006 

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    Event date: 2006.7.13 - 2006.7.14

    Venue:東京  

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  • Adenoviral gene therapy using NC1 domain of collagen IV suppresses vessel formation and tumor growth

    Toru Miyoshi, *Satoshi Hirohata, Hiroko Ogawa, Tomoko Yonezawa, Masanari Obika, Kadir Demircan,Yoshikazu Sado, Shozo Kusachi, Toshitaka Oohashi, Yasushi Shiratori, Billy G. Hudson, Yoshifumi Ninomiya

    欧州結合組織連合学術集会(FECTS)  2006 

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    Event date: 2006.7.1 - 2006.7.5

    Venue:フィンランド オウル市  

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  • Expression Profile of ADAMTS-aggrecanases in Head and Neck Squamous Cell Carcinomas

    Kadir Demircan, Mehmet Gunduz, *Satoshi Hirohata, Levent Beder, Esra Gunduz, Hitoshi Nagatsuka, Beyhan Cengiz, Toshitaka Oohashi, Omer F. Hatipoglu, Kenji Shimizu, Yoshifumi Ninomiya

    欧州結合組織連合学術集会(FECTS)  2006 

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    Event date: 2006.7.1 - 2006.7.5

    Venue:フィンランド オウル市  

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  • Aggrecanase member of ADAMTS proteases are differently regulated in ventricular remodeling

    *Satoshi Hirohata, Hiroko Ogawa, Tomoko Yonezawa, Toshitaka Oohashi, Shozo Kusachi, Kengo F. Kusano, Yasushi Shiratori, Tohru Ohe, Yoshifumi Ninomiya

    第20回国際生化学・分子生物学会議 (IUBMB)  2006 

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    Event date: 2006.6.19 - 2006.6.23

    Venue:京都市  

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  • Hyaluronan induced cytokine expression in peripheral blood mononuclear cells

    Hitoshi Yamawaki, *Satoshi Hirohata, Hiroko Ogawa, Masanari Obika, Kunihiko Hatanaka, Mutsumi Iwamoto, Shozo Kusachi, Yasushi Shiratori, Tomoko Yonezawa, Toshitaka Oohashi, Yoshifumi Ninomiya

    グライコマトリックス国際シンポジウム(Extracellular Glycomatrix in Health and Disease Symposium)  2006 

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    Event date: 2006.6.15 - 2006.6.17

    Venue:兵庫県淡路市  

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  • 無痛性甲状腺炎にて急性増悪したと考えられる拡張型心筋症の一例

    上杉 忠久、廣田 稔、大西 弘倫、野上 邦夫、武田 光、*廣畑 聡

    第88回日本循環器学会中国四国合同地方会  2006 

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    Event date: 2006.6.2 - 2006.6.3

    Venue:岡山市  

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  • 待機的PCI施行中に左冠動脈主幹部閉塞を呈した一例

    廣田 稔、野上 邦夫、上杉 忠久、大西 弘倫、武田 光、*廣畑 聡

    第88回日本循環器学会中国四国合同地方会  2006 

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    Event date: 2006.6.2 - 2006.6.3

    Venue:岡山市  

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  • 留置後9ヶ月で血栓性閉塞をきたしたcovered stentの一症例

    大西 弘倫、廣田 稔、上杉 忠久、野上 邦夫、武田 光、*廣畑 聡

    第88回日本循環器学会中国四国合同地方会  2006 

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    Event date: 2006.6.2 - 2006.6.3

    Venue:岡山市  

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  • Tumor-specific expression of the noncollagenous domain-1 of collagen IV suppresses endothelial tube formation and tumor growth in mice

    *Satoshi Hirohata, Hiroko Ogawa, Tomoko Yonezawa, Yoshikazu Sado, Shozo Kusachi, Toshitaka Oohashi, Billy G. Hudson, Yoshifumi Ninomiya

    第38回日本結合組織学会学術大会  2006 

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    Event date: 2006.5.27 - 2006.5.28

    Venue:前橋市  

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  • Cytokine-induced ADAMTS9 expression is inhibited by NF kappa beta inhibitors in chondrocytic cells

    Kadir Demircan, *Satoshi Hirohata, Cilek Mehmet Zeynel, Yoshifumi Ninomiya

    第53回マトリックス研究会大会  2006 

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    Event date: 2006.3.25 - 2006.3.26

    Venue:神奈川県箱根町  

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  • Changes in Serum Interferon-gamma Inducible Protein 10(IP-10) Levels Correlated with Ventricular Function and Infarct Size in Acute Myocardial Infarction Patients

    小天和也, *廣畑 聡, 丸山昌彦、岩本睦、山脇 均、小比賀真就、小川弘子、草地省蔵、白鳥康史、大江透

    第70回日本循環器学会学術集会  2006 

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    Event date: 2006.3.24 - 2006.3.26

    Venue:名古屋市  

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  • Architectural Change in the Neovessels in Infarct Border Zone after Myocardial Infarction by Scanning Electron Microscopy: Impact of Statin Treatment

    丸山昌彦、*廣畑 聡, 小天和也、小比賀真就、小川弘子、草地省蔵、白鳥康史、大江透

    第70回日本循環器学会学術集会  2006 

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    Event date: 2006.3.24 - 2006.3.26

    Venue:名古屋市  

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  • バーシカンはラット心筋梗塞において一時的に上昇し、その発現は再潅流障害により増強する

    *廣畑 聡、小川弘子 、山脇 均、小比賀真就、草地省蔵、白鳥康史、大江 透、二宮善文.

    第37回日本動脈硬化学会総会  2005 

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    Event date: 2005.7.14 - 2005.7.15

    Venue:東京  

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  • HyaluronanはCD44を介しcytokine分泌と共に細胞外matrix発現促進に働く:炎症時に単球で働くmatricrine機構

    山脇 均、*廣畑 聡、小川弘子、小比賀真就、草地省蔵、白鳥康史、大江 透

    第86回日本循環器学会中国地方会  2005 

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    Event date: 2005.5.29

    Venue:出雲  

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  • GM-CSF刺激により、ヒト末梢血単核球におけるバーシカンの発現は増加する

    山脇 均、*廣畑 聡、小比賀真就、小川弘子、大橋俊孝、草地省蔵、二宮善文

    第37回日本結合組織学会学術大会  2005 

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    Event date: 2005.5.27 - 2005.5.28

    Venue:富山市  

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  • Evidence for the Proteolytic Cleavage of Versican in Infarct Heart

    Masahiko Maruyama, *Satoshi Hirohata, Kazuya Koten, Hiroko Ogawa, Keigo Nakamura, Toru Miyoshi, Takashi Murakami, Yasushi Shiratori, Shozo Kusachi, Toru Ohe

    第69回日本循環器学会総会  2005 

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    Event date: 2005.3.19 - 2005.3.21

    Venue:横浜市  

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  • Increase in Connective Tissue Growth Factor (CTGF) Expression Precedes Extrracellular Matrix (ECM) Gene Expressions in Pressure-overload Heart in Rats

    Mutsumi Iwamoto, *Satoshi Hirohata, Hiroko Ogawa, Kazuya Koten, Masahiko Maruyama, Yasushi Shiratori, Shozo Kusachi, Toru Ohe.

    第69回日本循環器学会総会  2005 

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    Event date: 2005.3.19 - 2005.3.21

    Venue:横浜市  

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  • Lp3/Hapln3 Expression is Coordinately Upregulated with Versican in Balloon-injured Artery and is Enhanced by PDGF in Arterial Smooth Muscle Cell.

    Hiroko Ogawa, *Satoshi Hirohata, Takashi Murakami, Masanari Obika, Norihisa Toh, Yasushi Shiratori, Shozo Kusachi, Toru Ohe.

    第69回日本循環器学会総会  2005 

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    Event date: 2005.3.19 - 2005.3.21

    Venue:横浜市  

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  • Matricellular Protein Thrombospondin-1 (TSP-1) Enhances the Release of Inflammatory Cytokine Interleukin-6 in LPS and PMA-stimulated Human Peripheral Blood Mononuclear Cells

    Masanari Obika, *Satoshi Hirohata, Toru Miyoshi, Kazuya Koten, Masahiko Maruyama, Norihisa Toh, Yasushi Shiratori, Toru Ohe, Shozo Kusachi

    第69回日本循環器学会総会  2005 

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    Event date: 2005.3.19 - 2005.3.21

    Venue:横浜市  

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  • IL-1 and TNF- Induced expression of ADAMTS9 in chondrosarcoma cells is inhibited by MAPK inhibitors, SB203580 and PD98059.

    Kadir Demircan, *Satoshi Hirohata, Toshitaka Oohashi, Tomoko Yonezawa Yoshifumi Ninomiya.

    第52回マトリックス研究会大会  2005 

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    Event date: 2005.3.19 - 2005.3.20

    Venue:大分県大分郡湯布院町  

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  • ADAMTS9 is synergistically induced by IL-1 and TNF- in OUMS-27 chondrosarcoma cells and in human chondrocytes.

    Kadir Demircan, *Satoshi Hirohata, Keiichiro Nishida, Omer F. Hatipoglu, Toshitaka Oohashi, Tomoko Yonezawa, Suneel S. Apte and Yoshifumi Ninomiya

    第18回日本軟骨代謝学会  2005 

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    Event date: 2005.3.18 - 2005.3.19

    Venue:大阪府豊中市  

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  • Lp3/Hapln3, a novel link protein which colocalizes with versican and is coordinately upregulated by PDGF.

    Toshitaka Oohashi, Hiroko Ogawa, Masataka Sata, *Satoshi Hirohata, Yoshifumi Ninomiya

    Second National Meeting of the American Society for Matrix Biology  2004 

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    Event date: 2004.11.10 - 2004.11.13

    Venue:サンディゴ  

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  • Dynamic Induction of ADAMTS1 Gene in the Early Phase of Acute Myocardial Infarction

    *Satoshi Hirohata, Keigo Nakamura, Takashi Murakami, Toru Miyoshi, Kadir Demircan, Toshitaka Oohashi, Hiroko Ogawa, Kazuya Koten, Kenichi Toeda, Shozo Kusachi, Yoshifumi Ninomiya, Yasushi Shiratori

    Second National Meeting of the American Society for Matrix Biology  2004 

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    Event date: 2004.11.10 - 2004.11.13

    Venue:サンディエゴ  

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  • Endothelial Cells of Newly Formed Vessels Express Connective Tissue Growth Factor (CTGF), Osteonectin and Osteopontin mRNAs in the Border Zone of Myocardial Infarction in Rats

    *Satoshi Hirohata, Toru Miyoshi, Takashi Murakami, Masayuki Doi, Satoshi Sezaki, Shozo Kusachi, Yasushi Shiratori, Toru Ohe

    アメリカ心臓病協会(AHA)年次集会  2004 

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    Event date: 2004.11.7 - 2004.11.10

    Venue:ニューオーリンズ  

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  • Hapln3 Is a Novel Extracellular Matrix Protein Limited To Vessels and Is Upregulated in Pressure Overload Heart

    Hiroko Ogawa, *Satoshi Hirohata, Takashi Murakami, Keigo Nakamura, Toru Miyoshi, Shozo Kusachi, Yasushi Shiratori, Toru Ohe

    アメリカ心臓病協会(AHA)年次集会  2004 

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    Event date: 2004.11.7 - 2004.11.10

    Venue:ニューオーリンズ  

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  • 軟骨細胞におけるIL-1βとTNF-αによるアグリカナーゼ遺伝子発現誘導の多様性

    Kadir Demircan, *廣畑 聡、Omer F. Hatipoglu, 大橋俊孝、米澤朋子、二宮善文

    第77回日本生化学会大会  2004 

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    Event date: 2004.10.13 - 2004.10.16

    Venue:横浜市  

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  • 血管傷害モデルにおけるヒアルロン酸結合リンクプロテインLp3/Hapln3の発現解析

    小川弘子、大橋俊孝、佐田政隆、別宮洋子、*廣畑 聡、二宮善文

    第77回日本生化学会大会  2004 

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    Event date: 2004.10.13 - 2004.10.16

    Venue:横浜市  

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  • 新規マトリックスリンクプロテインLp3/Hapln3: クローニングおよびその発現解析

    小川弘子、大橋俊孝、*廣畑 聡、佐田政隆、村上充、二宮善文、草地省蔵、白鳥康史、大江透

    第36回日本動脈硬化学会総会  2004 

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    Event date: 2004.7.23 - 2004.7.24

    Venue:福岡市  

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  • Aggrecanases are differently regulated by IL-1b and TNF-a in chondrosarcoma cell line.

    K. Demircan, *S. Hirohata, T. Oohashi, T. Yonezawa, Y. Ninomiya

    欧州結合組織連合学術集会(FECTS)  2004 

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    Event date: 2004.7.10 - 2004.7.13

    Venue:タオルミーナ(イタリア)  

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  • Identification and Characterization of a novel rat link protein: Lp3/Hapln3

    小川弘子、村上充、大橋俊孝、*廣畑 聡、佐田政隆、三好亨、草地省蔵、白鳥康史、二宮善文

    第83回日本循環器学会中国地方会  2004 

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    Event date: 2004.5.22

    Venue:倉敷市  

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  • Vasl1 (Vascular Link Protein-1) Is a Novel Extracellular Matrix Protein Limited To Vessels and Is Upregulated in Pressure Overload Heart

    Hiroko Maeda, *Satoshi Hirohata, Takashi Murakami, Keigo Nakamura, Toru Miyoshi, Shozo Kusachi, Yasushi Shiratori, Toru Ohe

    第68回日本循環器学会総会  2004 

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    Event date: 2004.3.27 - 2004.3.29

    Venue:東京  

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  • ADAMTS-1, A Disintegrin And Metalloprotease with ThromboSpondin motifs-1, Is a Novel Hypoxic Immediate Gene Expressed by Endothelial Cells

    Keigo Nakamura, *Satoshi Hirohata, Takashi Murakami, Toru Miyoshi, Masayuki Doi, Shozo Kusachi, Yasushi Shiratori, Toru Ohe

    第68回日本循環器学会総会  2004 

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    Event date: 2004.3.27 - 2004.3.29

    Venue:東京  

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  • Serum Antibodies to Human Heat Shock Protein 60 Is Elevated in Subjects With Unstable Angina Pectoris

    Hiroshi Kawamura, Takashi Murakami, Tadahisa Uesugi, Nobuhiko Ohnishi, Atsushi Takaishi, Masayuki Ueeda, *Satoshi Hirohata, Takefumi Oka, Shozo Kusachi, Yasushi Shiratori, Toru Ohe

    第68回日本循環器学会総会  2004 

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    Event date: 2004.3.27 - 2004.3.29

    Venue:東京  

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  • Increments of serum chemokine interferon-gamma inducible protein 10 (IP-10) levels correlated with left ventricular function in acute myocardial infarction patients

    Kazuya Koten, Takashi Murakami, *Satoshi Hirohata, Satoshi Sezaki, Masahiko Maruyama, Shozo Kusachi, Yasushi Shiratori, Toru Ohe.

    第68回日本循環器学会総会  2004 

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    Event date: 2004.3.27 - 2004.3.29

    Venue:東京  

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  • Newly formed relatively large vessels after myocardial infarction express matricellular protein, Thrombospomndin-1 (TSP-1) in rats: Comparison with real-time RT-PCR analysis

    Satoshi Sezaki, *Satoshi Hirohata, Takashi Murakami, Masayuki Doi, Masahiko Maruyama, Hiroko Maeda, Shozo Kusachi, Yasushi Shiratori, Toru Ohe

    第68回日本循環器学会総会  2004 

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    Event date: 2004.3.27 - 2004.3.29

    Venue:東京  

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  • Low dose of Cerivastatin increased microvessel formation and induced angiogenesis in conjunction with attenuating anti-angiogenic protein in rat myocardial infarction

    *Satoshi Hirohata, Takashi Murakami, Masayuki Doi, Satoshi Sezaki, Shozo Kusachi, Yasushi Shiratori, Toru Ohe

    第68回日本循環器学会総会  2004 

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    Event date: 2004.3.27 - 2004.3.29

    Venue:東京  

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  • ADAMTS-1, A disintegrin and metalloprotease with thrombospondin motifs-1, is a novel hypoxic immediate gene expressed by endothelial cells.

    *Satoshi Hirohata, Takashi Murakami, Keigo Nakamura, Masayuki Doi, Shozo Kusachi, Yoshifumi Ninomiya, Yasushi Shiratori

    アメリカ心臓病協会(AHA)年次集会  2003 

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    Event date: 2003.11.9 - 2003.11.12

    Venue:オーランド  

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  • Identification of the novel rat Vascular link protein, Vasl1

    Hiroko Ogawa, Toshitaka Oohashi, Yoko Bekku, *Satoshi Hirohata, Yasushi Shiratori, Yoshifumi Ninomiya

    第76回日本生化学会大会  2003 

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    Event date: 2003.10.15 - 2003.10.18

    Venue:横浜市  

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  • Expression of Versican and its Degrading Enzymes in Acute Myocardial Infarction

    *Satoshi Hirohata, Takashi Murakami, Masayuki Doi, Shozo Kusachi, Tomoko Yonezawa, Toshitaka Oohashi, Yasushi Shiratori, Yoshifumi Ninomiya

    5th Pan-Pacific Connective Tissue Societies Symposium (PCTSS)  2003 

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    Event date: 2003.6.3 - 2003.6.7

    Venue:Ube, Yamaguchi, Japan  

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  • スタチンによる心筋梗塞後の血管新生誘導は血管新生阻害因子制御を介している

    中村 圭吾、*廣畑 聡、村上 充、土井 正行、草地 省蔵、白鳥 康史

    第82回日本循環器学会中国地方会  2003 

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    Event date: 2003.5.24

    Venue:広島市  

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  • Differential expression of ADAM-TS family members in osteosarcoma cell line (OUMS-27)

    Demircan K., *Hirohata S., Ninomiya Y

    第44回日本生化学会 中国四国支部例会  2003 

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    Event date: 2003.5.16 - 2003.5.17

    Venue:岡山市  

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  • Metalloprotease ADAMTS-1 Was Rapidly Expressed by Endothalial Cells in Acute Myocardial Infarction and Its Quantitative Analysis by Real-Time PCR

    中村圭吾, *廣畑 聡, 村上 充, 瀬崎 悟之, 土井 正行, 草地 省蔵、白鳥康史

    第67回日本循環器学会総会  2003 

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    Event date: 2003.3.28 - 2003.3.30

    Venue:福岡市  

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  • Late Reperfusion Enhanced Gelatinolysis in Infarct Periphreral Zone: Analysis by in Situ Zymogram Analysis in Rats

    三好 亨、村上 充、末澤 知聡、小天 和也、土井 正行, 瀬崎 悟之, *廣畑 聡, 草地 省蔵、白鳥康史

    第67回日本循環器学会総会  2003 

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    Event date: 2003.3.28 - 2003.3.30

    Venue:福岡市  

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  • Endothelial Cells of Newly Formed Vessels in the Border Zone of Myocardial Infarction Express Proteoglycan Decorin and Biglycan

    小天 和也、*廣畑 聡, 土井 正行,村上 充, 小松原一正、中村圭吾, 瀬崎 悟之, 丸山昌彦、草地 省蔵、白鳥康史

    第67回日本循環器学会総会  2003 

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    Event date: 2003.3.28 - 2003.3.30

    Venue:福岡市  

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  • 胆嚢炎に続発した感染性腹部大動脈瘤の一例

    三好 亨、廣畑 敦、小天 和也、土井 正行、*廣畑 聡、瀬崎 悟之、村上 充、草地 省蔵、白鳥 康史

    第81回日本循環器学会中国四国合同地方会  2002 

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    Event date: 2002.11.29 - 2002.11.30

    Venue:松江市  

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  • LAMININ-10: migration promoting activity on vascular endothelial cell

    土井 正行、村上 充、*廣畑 聡、中村 圭吾、草地 省蔵、白鳥 康史

    第80回日本循環器学会中国地方会  2002 

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    Event date: 2002.5.25

    Venue:米子市  

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  • Rapid increase of matrix adhesive glyocprotein, thrombospondin-1 (TSP-1) mRNA in rat myocardial infarction (MI) and its localization

    十枝 健一、*廣畑 聡、村上 充、中村 圭吾、竹本 俊二、瀬崎 悟之、草地 省蔵、辻 孝夫

    第66回日本循環器学会総会  2002 

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    Event date: 2002.4.24 - 2002.4.26

    Venue:札幌市  

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  • Chemokine Receptor CXCR-3 Was Up-regulated in Rat Myocardial Infarction(MI): Anasysis of cDNA Array and Quantitative Expression by Real Time PCR

    岩本 睦、*廣畑 聡、村上 充、竹本 俊二、中村 圭吾、小松原 一正、草地 省蔵、辻 孝夫

    第66回日本循環器学会総会  2002 

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    Event date: 2002.4.24 - 2002.4.26

    Venue:札幌市  

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  • Tissue Inhibitor of Metalloproteinase-2 Localization in Myocardial Infarction (MI) in Rats: Another Role as an Activator for Metalloproteinase-2

    竹本 俊二、村上 充、*廣畑 聡、瀬崎 悟之、草地 省蔵、辻 孝夫

    第66回日本循環器学会総会  2002 

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    Event date: 2002.4.24 - 2002.4.26

    Venue:札幌市  

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  • Endothelial Cells of Newly Formed Vessels Express Osteonectin mRNAs in the Border Zone of Myocardial Infarction (MI) in Rats

    瀬崎 悟之、*廣畑 聡、竹本 俊二、村上 充、前田 弘子、岩部 明弘、小松原 一正、草地 省蔵、辻 孝夫

    第66回日本循環器学会総会  2002