| Project/Area Number |
16590683
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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 | Osaka University |
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Principal Investigator |
OTSU Kinya Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (20294051)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Kazuhiro Osaka University, Center for Advanced Medical Engineering and Information, Specially Appointed Associate Professor, 臨床医工学融合研究教育センター, 特任助教授 (90303966)
NISHIDA Kazuhiko Osaka University, Graduate School of Dentistry, Assistant, 歯学研究科, 助手 (90362681)
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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 |
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | heart failure / reactive oxygen species / ASK1 / apoptosis / 遺伝子治療 / 細胞死 / 心不全モデル動物 |
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| Research Abstract |
We have previously reported that ASK1 plays an important role in pathogenesis of heart failure using its knockout mice. Here, we generated cardiac specific p38, a downstream kinase of ASK1 in the signaling cascade, knockout mice. The p38 knockout mice showed no phenotypic changes but pressure overload by means of transverse aortic constriction induced cardiac dilatation and dysfunction. Cardiac specific Raf-1 knockout mice exhibited heart failure not mediated through MEK/ERK but ASK1. Furthermore, we found that ASK1 ablation protected hearts from ischemia-reperfusion injury, in which necrosis is a major cell death form. Thus, ASK1 plays a role not only apoptosis but also necrosis.
We generated tamoxifen-induced cardiac specific ASK1 transgenic mice. Upon administration of tamoxifen, the transgenic mice exhibited cardiac dilatation and dysfunction with in one week. This confirms the role of ASK1 in pathogenesis of heart failure. Next, BIO TO-2 cardiomyopathic hamsters were subjected to transcoronary in vivo gene delivery of recombinant adeno-associated virus expressing a dominant-negative mutant of ASK1. The in vivo gene delivery of dominant-negative ASK1 attenuated ASK1 activation in cardiomyopathic hearts, progression of cardiac remodeling and preserved cardiac function. Suppression of ASK1 activity can be a novel therapeutic strategy for treatment of heart failure.
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