研究者詳細 - 三好　亨

論文 - 三好　亨

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Microarray analysis of gene expression in mouse aorta reveals role of the calcium signaling pathway in control of atherosclerosis susceptibility. 国際誌

Zuobiao Yuan, Toru Miyoshi, Yongde Bao, Jason P Sheehan, Alan H Matsumoto, Weibin Shi

American journal of physiology. Heart and circulatory physiology 296 ( 5 ) H1336-43 2009年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit a marked difference in atherosclerotic lesion formation when deficient in apolipoprotein E (apoE(-/-)), and the arterial wall has been identified as a source of the difference in atherosclerosis susceptibility. In the present study, differences in gene expression in aortic walls of the two strains were analyzed by microarrays. Total RNA was extracted from the aorta of 6-wk-old female B6 and C3H apoE(-/-) mice fed a chow or Western diet. There were 1,514 genes in chow fed mice and 590 genes in Western fed mice that were found to be differentially expressed between the two strains. Pathway analysis of differentially expressed genes suggested a role for the calcium signaling pathway in regulating atherosclerosis susceptibility. Oxidized LDL (oxLDL) induced a dose-dependent rise in cytosolic calcium levels in B6 endothelial cells. oxLDL-induced monocyte chemoattractant protein-1 production was inhibited by pretreatment with calcium chelator EGTA or intracellular calcium trapping compound BAPTA, indicating that calcium ions mediate the effect of oxLDL on monocyte chemoattractant protein-1 induction. The present findings demonstrate involvement of the calcium signaling pathway in the inflammatory process of atherogenesis.

DOI： 10.1152/ajpheart.01095.2008

Relationship between activin A level and infarct size in patients with acute myocardial infarction undergoing successful primary coronary intervention. 国際誌

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

Clinica chimica acta; international journal of clinical chemistry 401 ( 1-2 ) 3 - 7 2009年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.1016/j.cca.2008.10.027

Hyaluronan receptors involved in cytokine induction in monocytes. 国際誌

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年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

DOI： 10.1093/glycob/cwn109

Increased augmentation index of the radial pressure waveform in patients with paroxysmal atrial fibrillation. 国際誌

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 - 45 2009年

記述言語：英語掲載種別：研究論文（学術雑誌）

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 < 0.001). In all subjects, an increase in the augmentation index was significantly correlated with LV hypertrophy and left atrial enlargement. 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 < 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.

DOI： 10.1159/000177951

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 : official journal of the Japanese Circulation Society 72 ( 11 ) 1836 - 43 2008年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

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<0.0001 and r=-0.377, p<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.

Quantitative trait locus analysis of circulating adhesion molecules in hyperlipidemic apolipoprotein E-deficient mice. 国際誌

Zuobiao Yuan, Zhiguang Su, Toru Miyoshi, Jessica S Rowlan, Weibin Shi

Molecular genetics and genomics : MGG 280 ( 5 ) 375 - 83 2008年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Circulating soluble adhesion molecules have been suggested as useful markers to predict several clinical conditions such as atherosclerosis, type 2 diabetes, obesity, and hypertension. To determine genetic factors influencing plasma levels of soluble vascular cell adhesion molecule-1 (VCAM-1) and P-selectin, quantitative trait locus (QTL) analysis was performed on an intercross between C57BL/6J (B6) and C3H/HeJ (C3H) mouse strains deficient in apolipoprotein E-deficient (apoE-/-). Female F2 mice were fed a western diet for 12 weeks. One significant QTL, named sVcam1 (71 cM, LOD 3.9), on chromosome 9 and three suggestive QTLs on chromosomes 5, 13 and 15 were identified to affect soluble VCAM-1 levels. Soluble P-selectin levels were controlled by one significant QTL, named sSelp1 (8.5 cM, LOD 3.4), on chromosome 16 and two suggestive QTLs on chromosomes 10 and 13. Both adhesion molecules showed significant or an apparent trend of correlations with body weight, total cholesterol, and LDL/VLDL cholesterol levels in the F2 population. These results indicate that plasma VCAM-1 and P-selectin levels are complex traits regulated by multiple genes, and this regulation is conferred, at least partially, by acting on body weight and lipid metabolism in hyperlipidemic apoE-/- mice.

DOI： 10.1007/s00438-008-0371-0

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 - 8 2008年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

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 and 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 LV diastolic dysfunction. CONCLUSION: The present study revealed that an increased CAVI was independently associated with LV diastolic dysfunction in patients with preserved systolic function.

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年10月

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年10月

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 : official journal of the Japanese Circulation Society 72 ( 9 ) 1460 - 4 2008年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

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 >50% diameter stenosis of the PV in 11 (9%) patients before PVI (% diameter stenosis: mean 55+/-4%, range 51-65%). Greater than 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 on supine-position enhanced MDCT images. The results also indicate that preexisting PV organic stenosis is rare.

siRNA silencing reveals role of vascular cell adhesion molecule-1 in vascular smooth muscle cell migration. 国際誌

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

Atherosclerosis 198 ( 2 ) 301 - 6 2008年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

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 48h 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.

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年3月

Association of a Vcam1 mutation with atherosclerosis susceptibility in diet-induced models of atherosclerosis. 国際誌

Toru Miyoshi, Zuobiao Yuan, Weibin Shi

Atherosclerosis 196 ( 1 ) 234 - 239 2008年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

We previously identified a G>A single nucleotide polymorphism (SNP) between C57BL/6J (B6) and C3H/HeJ (C3H) mouse strains at position 2077 in the coding region of Vcam1 that leads to substitution of an amino acid from aspartic acid (D) to asparagine (N) in the protein product. In the present study, we investigated the association of this SNP with atherosclerosis susceptibility using a panel of inbred mouse strains, a set of recombinant inbred (RI) strains derived from B6 and C3H mice, and a cohort of F2 mice derived from B6 and C3H apolipoprotein E-deficient (apoE(-/-)) mice. Inbred strain analysis revealed that mouse strains with the B6 Vcam1 genotype developed significantly larger atherosclerotic lesions than strains with the C3H genotype (4622+/-2816 microm(2)/section versus 362+/-697 microm(2)/section; P=0.029). BXH RI strains with the B6 Vcam1 genotype also developed larger atherosclerotic lesions than those with the C3H genotype (8305+/-9031 microm(2)/section versus 2139+/-2931 microm(2)/section) although the difference was not statistically significant (P=0.13). In contrast, no association was detected between Vcam1 and atherosclerotic lesion size in F2 mice. The present data indicate that the G>A mutation of Vcam1 is associated with atherosclerotic lesion formation in the dietary but not apoE(-/-) models of atherosclerosis and this association suggests a role for the Vcam1 gene in influencing atherosclerosis susceptibility.

DOI： 10.1016/j.atherosclerosis.2007.05.004

Serum interferon-gamma-inducible protein 10 level was increased in myocardial infarction patients, and negatively correlated with infarct size. 国際誌

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 - 7 2008年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

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.

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年10月

Paradoxical increase in LDL oxidation by endothelial cells from an atherosclerosis-resistant mouse strain. 国際誌

Toru Miyoshi, Alan H Matsumoto, Weibin Shi

Atherosclerosis 192 ( 2 ) 259 - 65 2007年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Oxidative modification of LDL accumulated in the subendothelial space is a critical step in atherogenesis. Mouse strains C57BL/6 (B6) and BALB/c differ markedly in atherosclerosis susceptibility. We sought to determine whether variation of endothelial cells in the capacity to oxidize LDL or in response to minimally modified LDL (MM-LDL) constitutes a genetic component in atherosclerosis. LDL oxidation was assessed by measuring thiobarbituric acid-reactive substance (TBARS) production. Responses to MM-LDL were evaluated by examining induction of monocyte chemotactic protein-1, macrophage-colony stimulating factor, and vascular cell adhesion molecule-1. Both strains exhibited comparable endothelial responses to MM-LDL, whereas BALB/c mice had an increased rate of oxidizing LDL compared with B6 mice. To examine whether endothelial nitric oxide synthase (eNOS) contributed to the difference in LDL oxidation, cells were incubated with native LDL in the presence or absence of N(Omega)-nitro-l-arginine methyl ester (l-NAME), a specific NOS inhibitor. Although l-NAME significantly inhibited endothelial cell-mediated LDL oxidation, it failed to abolish the difference between the strains. In contrast, Baicalein, a specific 12/15 lipoxygenase inhibitor, abolished the difference in LDL oxidation. Thus, the paradoxical increase in LDL oxidation by endothelial cells is attributable to higher oxidant activity of 12/15-lipoxygenase in BALB/c mice and endothelial cells appear unlikely to be a source of the resistance to atherosclerosis.

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年5月

Direct evidence for a crucial role of the arterial wall in control of atherosclerosis susceptibility. 国際誌

Hong Pei, Yinong Wang, Toru Miyoshi, Zhimin Zhang, Alan H Matsumoto, Gregory A Helm, George Tellides, Weibin Shi

Circulation 114 ( 22 ) 2382 - 9 2006年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit marked differences in atherosclerosis susceptibility. We sought to determine whether the difference in atherosclerosis susceptibility resides at the level of arterial walls. METHODS AND RESULTS: Thoracic aortic segments from 8-week-old female B6 and C3H apolipoprotein E-deficient mice were transplanted into the infrarenal aorta of 10-week-old female F1 mice. After transplantation, recipients were maintained on a chow diet for 16 weeks. The donor aortic segments of B6 mice developed significantly larger atherosclerotic lesions than those of C3H (44,983+/-11,702 versus 5600+/-4885 microm2 per section; P=0.011). Expression of vascular cell adhesion molecule (VCAM)-1 by endothelial cells was examined both in vitro and in vivo. B6 mice expressed significantly more VCAM-1 than their C3H counterparts. Sequence analysis of VCAM-1 cDNA revealed a nucleotide difference in the coding region that resulted in substitution of an amino acid in the protein product. CONCLUSIONS: These data provide direct proof that factors operating in the vessel wall, particularly endothelial cells, can serve as atherosclerosis modifiers and suggest a possibility for the contribution of VCAM-1 to atherosclerosis susceptibility.

Differential response of vascular smooth muscle cells to oxidized LDL in mouse strains with different atherosclerosis susceptibility. 国際誌

Toru Miyoshi, Jing Tian, Alan H Matsumoto, Weibin Shi

Atherosclerosis 189 ( 1 ) 99 - 105 2006年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Oxidized low-density lipoprotein (LDL) has numerous atherogenic properties, including induction of inflammatory genes, and vascular smooth muscle cells (VSMC) are involved in the development of atherosclerosis. In this study, we examined whether variations of VSMC in the capacity to oxidize LDL or in response to minimally modified LDL (MM-LDL) constitute a genetic component in atherosclerosis. VSMC were isolated from the aorta of two inbred mouse strains C57BL/6J (B6) and C3H, which differ markedly in susceptibility to atherosclerosis. LDL oxidation was assessed by measuring thiobarbituric acid-reactive substance (TBARS) production. Responses to MM-LDL were evaluated by examining the expression of inflammatory genes involved atherosclerosis, including monocyte chemotactic protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1), and an oxidant stress gene, heme oxygenase-1 (HO-1). VSMC from the two strains exhibited a comparable ability to transform native LDL to oxidized LDL, whereas their response to MM-LDL differed markedly. MM-LDL resulted in dramatic induction of MCP-1, VCAM-1, and HO-1 mRNAs in the cells from B6 mice but exerted little effect in cells from C3H mice. MCP-1 and soluble VCAM-1 protein levels in conditioned media were measured by ELISA. B6 cells produced significantly more MCP-1 and VCAM-1 proteins in response to MM-LDL than C3H cells. These data suggest that variation in the response of VSMC to oxidized LDL may contribute to the difference between B6 and C3H mice in atherosclerosis susceptibility.

Tumor-specific expression of the RGD-alpha3(IV)NC1 domain suppresses endothelial tube formation and tumor growth in mice. 国際誌

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 : official publication of the Federation of American Societies for Experimental Biology 20 ( 11 ) 1904 - 6 2006年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Angiogenesis plays an essential role in tumor growth. This study investigated expression of the noncollagenous domain of alpha3(IV) collagen (alpha3(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 alpha3(IV)NC1 (hTERT/RGD-alpha3(IV)NC1) were expressed in telomerase-expressing tumor cells, it would inhibit tumor growth by its anti-angiogenic property. Adenoviral transduction of hTERT/RGD-alpha3(IV)NC1 expressed RGD-alpha3(IV)NC1 in hTERT-positive tumor cell lines. However, hTERT/RGD-alpha3(IV)NC1 did not express RGD-alpha3(IV)NC1 in hTERT-negative cells such as keratinocytes and fibroblasts. The secreted RGD-alpha3(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-alpha3(IV)NC1 gene therapy showed limited expression of RGD-alpha3(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-alpha3(IV)NC1. In addition, long-term inhibition of tumor growth was achieved by intermittent administration of hTERT/RGD-alpha3(IV)NC1. In conclusion, our findings demonstrate that tumor-specific anti-angiogenic gene therapy utilizing RGD-alpha3(IV)NC1 under the hTERT promoter inhibited angiogenesis in tumors, resulting in an antitumor effect.

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