| Project/Area Number |
15590755
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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 |
KUBOTA Toru Kyushu University, Graduate School of Medical Sciences, Research Associate, 大学院・医学研究院, 助手 (40325444)
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| Co-Investigator(Kenkyū-buntansha) |
TSUTSUI Hiroyuki Hokkaido University, Graduate School of Medicine, Professor, 大学院・医学研究科, 教授 (70264017)
ICHIKI Toshihiro Kyushu University, Graduate School of Medical Sciences, Research Associate, 大学病院, 助手 (80311843)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | heart failure / cardiac hypertrophy / NF-κB / angiotensin / cytokine / genetically-engineered mice / サイトカン |
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| Research Abstract |
NF-κB is a key transaction factor that regulates inflammatory processes. Recent studies have demonstrated that NF-κB is activated in the failing human heart with augmented expression of proinflammatory cytokines. We therefore have investigated the role of NF-κB in three animal models of cardiac hypertrophy and remodeling. Mice with targeted disruption of the p50 subunit of NF-κB (KO) were used to block tie activation of NF-κB in vivo. (1)Chronic infusion of angiotensin II increased systemic blood pressure and provoked ventricular hypertrophy with activated NF-κB and proinflammatory cytokines, including TNF-α. The p50 KO blocked the activation of NF-κB and ameliorated ventricular hypertrophy despite augmented hypertension and enhanced expression of TNF-α. (2)NF-κB was activated in infarct as well as in non-infarct myocardium after ligation of left coronary artery. The p50 KO blocked the activation of NF-κB and ameliorated cardiac dysfunction four weeks after myocardial infarction. Expression of proinflammatory cytokines was rather enhanced by the p50 KO. (3)Transgenic mice with cardiac-specific overexpression of TNF-α developed myocardial inflammation with progressive ventricular hypertrophy and dilatation. Crossing with the p50 KO blocked tie activation of NF-κB and improved cardiac function and survival with inhibition of MMP-9 activity. The p50 KO did not ameliorate infiltration of inflammatory cells or expression of proinflammatory cytokines in TNF-α transgenic mice. In conclusion, the targeted disruption of the p50 subunit of NF-κB results in attenuation of cardiac hypertrophy and remodeling without diminishing proinflammatory cytokines in various animal models of heart failure. NF-κB might play an important role in the pathogenesis of heart failure besides promoting inflammation.
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