| Project/Area Number |
14370219
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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 | Chiba University |
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Principal Investigator |
MINAMINO Tohru Chiba University, hospital, Instructor, 医学部附属病院, 助手 (90328063)
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| Co-Investigator(Kenkyū-buntansha) |
KOMURO Issei Chiba University, Graduate School of Medicine, Professor, 大学院・医学研究院, 教授 (30260483)
TAKANO Hiroyuki Chiba University, Graduate School of Medicine, Instructor, 大学院・医学研究院, 助手 (60334190)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥7,600,000 (Direct Cost: ¥7,600,000)
Fiscal Year 2004: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2003: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2002: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Keywords | Cellular senescence / Vascular aging / Telomere / Ras / Angiotensin II / Insulin / Akt / p53 / p21 / 動脈硬化 / 動脈瘤 / 糖尿病 |
|---|
| Research Abstract |
Vascular cells have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest called "cellular senescence." We demonstrated the presence of senescent vascular cells in human atherosclerotic lesions but not non-atherosclerotic lesions. Moreover, these cells expressed increased levels of proinflammatory molecules and decreased levels of endothelial nitric oxide synthase, suggesting that cellular senescence in vivo contributes to the pathogenesis of human atherosclerosis and vascular aging. One widely discussed hypothesis of senescence is the telomere hypothesis. We showed a critical role of telomere function in regulating vascular function as well as lifespan of vascular cells. We also found that constitutive activation of Ras prematurely induced vascular cell senescence that is associated with vascular inflammation. Introduction of Ras into balloon-injured arteries enhanced vascular inflammation as well as senescence compared with control-injured arteri
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es. Moreover, senescent cells express inflammatory molecules in human atherosclerotic plaque, and ERK is activated in these cells, suggesting that telomere-independent mechanisms may also contribute to vascular cell senescence in human atherosclerosis. Angiotensin II (Ang II) is a potent activator for Ras and has been reported to contribute to the pathogenesis of various human vascular diseases. We found that Ang II promoted vascular inflammation by inducing cellular senescenee both in vitro and in vivo. Inhibition of senescence effectively prevented Ang II-induced vascular inflammation. Reduction-of-function mutations in components of the insulin/Akt pathway have been shown to extend the lifespan in organisms ranging from yeast to mice. We showed here that Akt activity increased with cellular senescence and that inhibition of Akt extended the lifespan of primary cultured human endothelial cells. Constitutive activation of Akt promoted senescence-like arrest of cell growth via a p53/p21-dependent pathway, leading to endothelial dysfunction. This novel role of Akt in regulating the cellular lifespan may contribute to various human, diseases including atherosclerosis and diabetes mellitus. Less
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