2006 Fiscal Year Final Research Report Summary
Clarification of the role of apoptosis in the formation of vascular lesion and application of apoptosis-inducing factor to the treatment of restenosis after stent implantation.
| Project/Area Number |
17590742
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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 UNIVERCITY |
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Principal Investigator |
ICHIKI Toshihiro Kyushu University Hospital, Department of Cardiovascular Medicine, Assistant Professor, 大学病院, 講師 (80311843)
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| Co-Investigator(Kenkyū-buntansha) |
EGASHIRA Kensuke Kyushu University, Gradate School of Medical Sciences, Associate Professor, 大学院医学研究院, 循環器内科・助教授 (60260379)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Mst1 / Apoptosis / vascular smooth muscle cell / endothelial cell / TNFα / balloon injury model of rat carotid artery / siRNA / ICER |
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| Research Abstract |
Mst1 is a serine/threonine kinase that is involved in the process of apoptosis. However, the role of Mstl in the blood vessel has not been reported to date. Stimulation of vascular smooth muscle cells (VSMCs) with staturosporine induced apoptosis as well as activation of Mstl. After balloon injury of rat carotid artery, the expression of Mstl was increased in the neointima. Overexpression of Mstl by an adenovirus vector in the injured rat carotid artery enhanced the number of TUNEL positive cells and reduced the extent of neointimal formation. We also found that tumor necrosis factor □ (TNF□) induced activation of Mstl in endothelial cells (ECs) through induction of reactive oxygen species. Knockdown of the Mstl expression by siRNA attenuated TNF□ -induced apoptosis of ECs.
We next examined the role of inducible cAMP early repressor (ICER), a transcription repressor, of which expression is induced by cAMP. Beraprost, a PGI2 derivative, induced the expression of ICER in VSMCs in a dose-and time-dependent manner. Beraprost inhibited platelet-derived growth factor-induced growth of VSMCs. Knockdown of ICER expression by siRNA attenuated the beraprost-induced growth suppression, suggesting that beraprost-induced growth suppression is, at least in part, mediated by induction of ICER. Overexpression of ICER by an adenovirus vector induced the apoptosis of VSMCs and inhibited neointimal formation after balloon injury of rat carotid artery.
These results suggest that it may be possible to inhibit growth of VSMCs by modulating the expression and/or activity of Mstl or ICER. These molcules may be applied to the treatment of vascular diseases such as atherosclerosis and in-stent restenosis.
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