研究者詳細 - 廣畑　聡

論文 - 廣畑　聡

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Suppression of nitric oxide synthase aggravates non-alcoholic steatohepatitis and atherosclerosis in SHRSP5/Dmcr rat via acceleration of abnormal lipid metabolism. 査読国際誌

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 74 ( 4 ) 669 - 683 2022年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

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. 査読国際誌

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

Biochimie 197 49 - 58 2022年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

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

Potential of a Novel Chemical Compound Targeting Matrix Metalloprotease-13 for Early Osteoarthritis: An In Vitro Study. 査読国際誌

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年2月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

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

Osteopontin silencing attenuates bleomycin-induced murine pulmonary fibrosis by regulating epithelial-mesenchymal transition. 査読国際誌

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 = Biomedecine & pharmacotherapie 139 111633 - 111633 2021年7月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier BV

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.

DOI： 10.1016/j.biopha.2021.111633

Low plasma apolipoprotein E-rich high-density lipoprotein levels in patients with metabolic syndrome. 査読国際誌

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

Clinica chimica acta; international journal of clinical chemistry 510 531 - 536 2020年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER

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

Efficacy of an Adjunctive Electrophysiological Test-Guided Left Atrial Posterior Wall Isolation in Persistent Atrial Fibrillation Without a Left Atrial Low-Voltage Area. 査読国際誌

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年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：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>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>
<sec>
<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

Induction of CEMIP in Chondrocytes by Inflammatory Cytokines: Underlying Mechanisms and Potential Involvement in Osteoarthritis. 査読国際誌

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

International journal of molecular sciences 21 ( 9 ) 2020年4月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：MDPI

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

Deficiency of CD44 prevents thoracic aortic dissection in a murine model. 査読国際誌

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年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

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

Mechanical strain attenuates cytokine-induced ADAMTS9 expression via transient receptor potential vanilloid type 1. 査読国際誌

Ohtsuki T, Shinaoka A, Kumagishi-Shinaoka K, Asano K, Hatipoglu OF, Inagaki J, Takahashi K, Oohashi T, Nishida K, Naruse K, Hirohata S

Experimental cell research 383 ( 2 ) 111556 - 111556 2019年10月

Serum malondialdehyde-modified low-density lipoprotein levels on admission predict prognosis in patients with acute coronary syndrome undergoing percutaneous coronary intervention 査読国際誌

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年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER

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

High molecular weight hyaluronan protects cartilage from degradation by inhibiting aggrecanase expression. 査読国際誌

Ohtsuki T, Asano K, Inagaki J, Shinaoka A, Kumagishi-Shinaoka K, Cilek MZ, Hatipoglu OF, Oohashi T, Nishida K, Komatsubara I, Hirohata S

J Orthop Res. 36 ( 12 ) 3247 - 3255 2018年12月

Non-alcoholic steatohepatitis aggravates nitric oxide synthase inhibition-induced arteriosclerosis in SHRSP5/Dmcr rat model 査読国際誌

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年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY

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.

DOI： 10.1111/iep.12301

Differences in activated clotting time and initial heparin dosage during atrial fibrillation ablation for patients with edoxaban compared with warfarin 査読国際誌

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年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Blackwell Publishing Inc.

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.

DOI： 10.1111/jce.13483

Host-produced ADAMTS4 Inhibits Early-Stage Tumor Growth. 査読

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年6月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.18926/AMO/56071

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

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年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Japan Atherosclerosis Society

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.

DOI： 10.5551/jat.40956

Stromal Versican Regulates Tumor Growth by Promoting Angiogenesis 査読国際誌

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年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

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.

DOI： 10.1038/s41598-017-17613-6

MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1 査読国際誌

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年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

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.

DOI： 10.1016/j.matbio.2016.03.007

Loss of ADAMTS4 reduces high fat diet-induced atherosclerosis and enhances plaque stability in ApoE(-/-) mice 査読国際誌

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年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

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.

DOI： 10.1038/srep31130

Interleukin-1β induced nuclear factor-κB binds to a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 9 promoter in human chondrosarcoma cells. 査読国際誌

Altuntas A, Halacli SO, Cakmak O, Erden G, Akyol S, Ugurcu V, Hirohata S, Demircan K

Molecular medicine reports 12 ( 1 ) 595 - 600 2015年7月

ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor. 査読国際誌

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年5月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.1016/j.yexcr.2014.03.002

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