Phosphatidylinositol 3-kinase γ is a critical mediator of myocardial ischemic and adenosine-mediated preconditioning

被引：65

作者：

Ban, Kiwon ^{[2
]}

Cooper, Andrew J. ^{[2
]}

Samuel, Sara ^{[1
]}

Bhatti, Adil

Patel, Mikin ^{[2
]}

Izumo, Seigo ^{[5
]}

Penninger, Josef M. ^{[6
]}

Backx, Peter H. ^{[2
,3
,4
]}

Oudit, Gavin Y. ^{[2
,3
,4
]}

Tsushima, Robert G. ^{[1
,2
,3
,4
]}

机构：

[1] York Univ, Dept Biol, Toronto, ON M3J 1P3, Canada

[2] Univ Toronto, Dept Physiol & Med, Toronto, ON M5S 1A1, Canada

[3] Univ Toronto, Dept Heart & Stroke, Richard Lewar Ctr Excellence, Toronto, ON M5S 1A1, Canada

[4] Univ Toronto, Div Cardiol, Toronto, ON M5S 1A1, Canada

[5] Novartis Inst Biomed Res, Basel, Switzerland

[6] Austrian Acad Sci, Inst Mol Biotechnol, A-1010 Vienna, Austria

来源：

CIRCULATION RESEARCH | 2008年 / 103卷 / 06期

关键词：

heart; ischemic preconditioning; PI3K; Akt; GSK3; beta; transgenic mice;

D O I：

10.1161/CIRCRESAHA.108.175018

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Ischemic preconditioning (IPC) is a potent cellular protective mechanism whereby brief periods of sublethal ischemia protect the myocardium from prolonged ischemia-induced injury. We demonstrate the selective role of phosphatidylinositol 3-kinase (PI3K) isoforms in IPC. Hearts from PI3K gamma knockout mice (PI3K gamma(-/-)) displayed poorer functional recovery and greater tissue injury following IPC compared to wild-type and PI3K gamma(-/)-hearts. Examination of the cell-signaling pathways revealed restored phosphorylation levels of Akt and glycogen synthase kinase (GSK) 3 beta in wild-type hearts, which were abolished in PI3K gamma(-/-) hearts subjected to IPC. Inhibition of GSK3 beta by LiCl reversed the loss in protection in PI3K gamma(-/-) hearts. In contrast, mice expressing a cardiac-specific kinase-deleted PI3K alpha (PI3K alpha DN) were resistant to injury induced by 30 minutes of ischemia followed by 40 minutes of reperfusion. Furthermore, the resistance of PI3K alpha DN hearts to ischemia/reperfusion correlated with the persistent expression of p110 gamma and was blocked by the PI3K inhibitor wortmannin, suggesting the possible enhanced cell signaling through the PI3K gamma pathway. These results demonstrate the importance of the PI3K gamma-Akt-GSK3 beta signaling pathway in IPC. Selective activation of myocardial PI3K gamma may be an attractive target for the treatment of ischemic heart disease.

引用

页码：643 / 653

页数：11

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