Aggravation mechanism of cardiac ischemia-reperfusion injury through oxidative stress-sensitive channel TRPM2
| Project/Area Number |
21590104
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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 |
Biological pharmacy
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| Research Institution | Showa University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
ISHII Masakazu 昭和大学, 薬学部, 准教授 (30307061)
根来 孝治 昭和大学, 薬学部, 講師 (70218270)
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| Co-Investigator(Renkei-kenkyūsha) |
NEGORO Takaharu 昭和大学, 薬学部, 准教授 (70218270)
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| Project Period (FY) |
2009 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2009: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | 虚血再灌流障害 / TRPM2 / カルシムイオン / 好中球 / 心臓 / 活性酸素 / Ca2+透過性チャネル / 虚血-再灌流障害 |
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| Research Abstract |
Aims. Transient receptor potential melastatin 2(TRPM2) is a Ca^<2+-> permeable nonselective cation channel activated by oxidative stress, and is expressed in neutrophils and cardiomyocytes. This study examined whether TRPM2 contributes to myocardial ischemia-reperfusion(I/R) injury, in which acute inflammation with oxidative stress is closely involved. Methods and Results. Wild-type(Trpm2^<+/+>) and Trpm2 knockout(Trpm2^<-/->) mice were exposed to I/R by ligation of the left coronary artery. Myocardial infarction following I/R but not ischemia alone was reduced in Trpm2^<-/-> mice compared to Trpm2^<+/+> mice, and cardiac contractile function was also improved in Trpm2^<-/-> mice. Moreover, neutrophil accumulation in the reperfused area was lowered in Trpm2^<-/-> mice. When Trpm2^<+/+> or Trpm2^<-/-> polymorphonuclear leukocytes(PMNs) were administered to the Trpm2^<-/-> heart ex vivo through perfusate or in vivo by intravenous injection, Trpm2^<+/+> PMNs induced more severe cardiac injury following I/R compared with Trpm^<2-/-> PMNs. In Trpm2^<+/+> but not in Trpm2^<-/-> PMNs, the combination of H_2O_2 and leukotriene B_4(LTB_4) resulted in enhancement of the increase in intracellular Ca^<2+> and their adhesion to endothelial cells. Conclusions. These findings indicate that TRPM2 is implicated in the development of myocardial reperfusion injury. Accumulation of neutrophils in the heart triggered by activation of neutrophil TRPM2 by H_2O_2 and LTB_4 is likely to have a crucial role in myocardial I/R injury.
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Report
(4 results)
Research Products
(5 results)
