Phosphatidylinositol 3-kinase gamma is a critical mediator of myocardial ischemic and adenosine-mediated preconditioning.
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 PI3Kgamma knockout mice (PI3Kgamma(-/-)) displayed poorer functional recovery and greater tissue injury following IPC compared to wild-type and PI3Kgamma(+/-) hearts. Examination of the cell-signaling pathways revealed restored phosphorylation levels of Akt and glycogen synthase kinase (GSK)3beta in wild-type hearts, which were abolished in PI3Kgamma(-/-) hearts subjected to IPC. Inhibition of GSK3beta by LiCl reversed the loss in protection in PI3Kgamma(-/-) hearts. In contrast, mice expressing a cardiac-specific kinase-deleted PI3Kalpha (PI3KalphaDN) were resistant to injury induced by 30 minutes of ischemia followed by 40 minutes of reperfusion. Furthermore, the resistance of PI3KalphaDN hearts to ischemia/reperfusion correlated with the persistent expression of p110gamma and was blocked by the PI3K inhibitor wortmannin, suggesting the possible enhanced cell signaling through the PI3Kgamma pathway. These results demonstrate the importance of the PI3Kgamma-Akt-GSK3beta signaling pathway in IPC. Selective activation of myocardial PI3Kgamma may be an attractive target for the treatment of ischemic heart disease.
Ban
Kiwon
K
Department of Medicine and Physiology, University of Toronto, Ontario, Canada.
Cooper
Andrew J
AJ
Samuel
Sara
S
Bhatti
Adil
A
Patel
Mikin
M
Izumo
Seigo
S
Penninger
Josef M
JM
Backx
Peter H
PH
Oudit
Gavin Y
GY
Tsushima
Robert G
RG
D000241:Adenosine / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D058544:Class Ib Phosphatidylinositol 3-Kinase; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D000241:Adenosine