Molecular Mechanisms of Vasa Vasorum Angiogenesis and Dysregulation of Vascular Smooth Muscle Cell Differentiation
| Project/Area Number |
16390216
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Gunma University |
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Principal Investigator |
KURABAYASHI Masahiko GUNMA UNIVERSITY, GRADUATE SCHOOL OF MEDICINE, PROFESSOR, 大学院・医学系研究科, 教授 (00215047)
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| Co-Investigator(Kenkyū-buntansha) |
ARAI Masashi GUNMA UNIVERSITY, FACULTY OF MEDICINE, LECTURER, 医学部, 講師 (60270857)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥14,200,000 (Direct Cost: ¥14,200,000)
Fiscal Year 2005: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 2004: ¥9,700,000 (Direct Cost: ¥9,700,000)
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| Keywords | Vascular smooth cell / Hypoxia / Atherosclerosis / Mitochondria / Artery / Gene expression / Signal transduction / チロシンキナーゼ / HIF-1α / 活性酸素種 / 血管新生 / PAI-1 |
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| Research Abstract |
Thickened atherosclerotic plaques are prone to be hypoxic because of poor perfusion. In this study, we tested the hypothesis that hypoxia produces reactive oxygen species (ROS) and activates c-Src tyrosine kinase in vascular smooth muscle cells (VSMC). Treatment of VSMCs with redox-sensitive probes, dihydroethidium and 2',7'-dihydrodichlorofluorescein diacetate, revealed that hypoxia increased intracellular superoxide anion and hydrogen peroxide (H_2O_2). Northern blot analysis showed that hypoxia-induced PAI-1 and VEGF genes expression was significantly inhibited by c-Src inhibitor PP1. Western blot analysis showed that hypoxia rapidly elicited tyrosine phosphorylation of c-Src. Induction of the PAI-1 and VEGF genes expression was significantly attenuated in c-Src-, Yes-, and Fyn-negative cells as compared with c-Src-overexpressing cells. Hypoxia-inducible HIF-1α protein expression was significantly attenuated by PP1, diphenyleneiodonium (DPI), and N-acetyl 1-cysteine. Rotenone and an
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timycin A, which inhibit the mitochondrial electron transport chain, abolished the HIF-1α induction by hypoxia. Treatment of VSMC with H_2O_2 induced HIF-1α protein even under normoxia. These results suggest that ROS and c-Src play a critical role in hypoxia-induced HIF-1α protein and PAI-1 and VEGF gene expression in VSMC. Our data also demonstrate that mitochondria act as the O_2 sensor mediating c-Src phosphorylation during hypoxia.
In addition, we determined the role of Notch target gene HERP1 in the regulation of phenotypic modulation of vascular SMC. The present study characterizes the expression of HERP1 in normal and diseased vessels, and tests the hypothesis that HERP1 inhibits SRF/myocardin-dependent SMC gene expression. Immunohistochemistry revealed that HERP1 and myocardin expression was localized to SMC of the neointima after balloon injury of rat aorta and in human coronary atherosclerotic lesions. Expression of both HERP1 and myocardin was markedly elevated in cultured VSMC compared with medial SMC. Overexpression of HERP1 dramatically inhibited the myocarin-induced SMC-marker gene expression. Immunoprecipitation assays showed that HERP1 physically interacts with SRF. Thus, we conclude that HERP1 may play a role in promoting the phenotypic modulation of VSMC during vascular injury and atherosclerotic process by interfering with SRF binding to CArG box through physical association between HERP1 and SRF. Less
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Report
(3 results)
Research Products
(16 results)
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[Journal Article] c-Src and hydrogen peroxide mediate transforming growth factor-betal-induced smooth muscle cell-gene expression in 10T1/2 cells.2005
Author(s)
Sato M, Kawai-Kowase K, Sato H, Oyama Y, Kanai H, Ohyama Y, Suga T, Maeno T, Aoki Y, Tamura J, Sakamoto H, Nagai R, Kurabayashi M
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Journal Title
Arterioscler Thromb Vasc Biol. 25(2)
Pages: 341-347
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] HERP1 inhibits myocardin-induced vascular smooth muscle cell differentiation by interfering with SRF binding to CArG box.2005
Author(s)
Doi H, Iso T, Yamazaki M, Akiyama H, Kanai H, Sato H, Kawai-Kowase K, Tanaka T, Maeno T, Okamoto E, Arai M, Kedes L, Kurabayashi M
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Journal Title
Arterioscler Thromb Vasc Biol. 25(11)
Pages: 2328-2334
Description
「研究成果報告書概要(欧文)」より
Related Report
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