2003 Fiscal Year Final Research Report Summary
Role of redox-sensitive transcription factor in the progression of atherosclerosis Possible application to gene therapy.
| Project/Area Number |
14570673
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | KYUSHU UNIVERSITY |
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Principal Investigator |
ICHIKI Toshihiro Kyushu University Hospital, Ass. PROF., 大学病院, 助手 (80311843)
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| Project Period (FY) |
2002 – 2003
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| Keywords | Reactive oxygen species / Transcription factors / mitogen activated protein kinase / epidermal growth factor receptor / transactivation / cAMP response element binding protein |
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| Research Abstract |
The aim of the present study is to identify redox-sensitive transcription factors and to analyze their role in the blood vessel. Angiotensin II that induces production of reactive oxygen species activated cAMP response element binding protein (CREB), a 43KDa nuclear transcription factor, in vascular smooth muscle cells. Hydrogen peroxide (1-1202) also activated CREB, (VSMC). H_2O_2 transiently activated CREB after 15 minutes of stimulation in ERK-and p38MAPK-dependent manner. An inhibitor for epidermal growth factor receptor (EGF-R) also suppressed H_2O_2-induced activation of CREB, suggesting that transactivation of EGF-R plays an important role in the activation of CREB. Indeed, H_2O_2 induced tyrosine phosphorylation of EGF-R. Activation of CREB by All was inhibited by N-acetylcysteine, a potent antioxidant, suggesting a critical role of reactive oxygen species in All signaling. These data suggest that CREB is a redox-sensitive transcription factor. Overexpression of dominant negative CREB by an adenovirus vector decreased Bcl-2 expression in VSMC and resulted in the induction of apoptosis. Infection of adenovirus expressing dominant negative CREB suppressed neointimal formation after balloon injury of rat carotid artery with an increase in TUNEL positive cells. These data suggest that CREB is an important redox-sensitive transcription factor that mediates survival and proliferation of VSMC. And it was suggested that CREB may be a novel therapeutic target to treat vascular diseases.
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