Published online before print August 7, 2008, doi: 10.1161/CIRCRESAHA.108.175018
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Submitted on March 2, 2008
Revised on July 24, 2008
Accepted on July 24, 2008
Phosphatidylinositol 3-Kinase 
Is a Critical Mediator of Myocardial Ischemic and Adenosine-Mediated Preconditioning
Kiwon Ban ;
From the Departments of Medicine and Physiology (K.B., A.J.C., M.P., P.H.B., G.Y.O., R.G.T.), Heart and Stroke/Richard Lewar Centre of Excellence (P.H.B., G.Y.O., R.G.T.), and Division of Cardiology (P.H.B., G.Y.O., R.G.T.), University of Toronto, Ontario, Canada; Department of Biology (S.S., R.G.T.), York University, Toronto, Ontario, Canada; Novartis Institutes for Biomedical Research (S.I.); and Institute of Molecular Biotechnology (J.M.P.), Austrian Academy of Sciences.
* To whom correspondence should be addressed. E-mail: tsushima{at}yorku.ca.
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
knockout mice (PI3K-/-) displayed poorer functional recovery and greater tissue injury following IPC compared to wild-type and PI3K+/- hearts. Examination of the cell-signaling pathways revealed restored phosphorylation levels of Akt and glycogen synthase kinase (GSK)3
in wild-type hearts, which were abolished in PI3K-/- hearts subjected to IPC. Inhibition of GSK3 by LiCl reversed the loss in protection in PI3K-/- hearts. In contrast, mice expressing a cardiac-specific kinase-deleted PI3K
(PI3KDN) were resistant to injury induced by 30 minutes of ischemia followed by 40 minutes of reperfusion. Furthermore, the resistance of PI3KDN hearts to ischemia/reperfusion correlated with the persistent expression of p110 and was blocked by the PI3K inhibitor wortmannin, suggesting the possible enhanced cell signaling through the PI3K pathway. These results demonstrate the importance of the PI3K-Akt-GSK3 signaling pathway in IPC. Selective activation of myocardial PI3K may be an attractive target for the treatment of ischemic heart disease.
Key words: heart • ischemic preconditioning • PI3K • Akt • GSK3
, transgenic mice
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