The role of PI3Kα isoform in cardioprotection

Ischemic preconditioning (IPC) limits myocardial infarct size through the activation of the PI3K-Akt signal cascade; however, little is known about the roles of individual PI3K isoforms in cardioprotection. We aimed, therefore, to elucidate the role of the PI3K alpha isoform in cardioprotection Pharmacological PI3K alpha inhibition was assessed in isolated-perfused mouse hearts subjected to ischemia/reperfusion injury (IRI), either during the IPC procedure or at reperfusion. PI3K alpha inhibition abrogated the IPC-induced protective effect at reperfusion, but not when given only during the IPC protocol. These results were confirmed in an in vivo model. Moreover, pharmacological PI3K alpha activation by insulin at reperfusion was sufficient to confer cardioprotection against IRI. In addition, PI3K alpha was shown to be expressed and activated in mouse cardiomyocytes, mouse cardiac endothelial cells, as well as in mouse and human heart tissue. Furthermore, PI3K alpha was shown to mediate its effect though the inhibition of mitochondrial permeability transition pore opening. In conclusion, PI3K alpha activity is required during the early reperfusion phase to reduce myocardial infarct size. This suggests that strategies specifically enhancing the alpha isoform of PI3K at reperfusion promote tissue salvage and as such, and could provide a direct target for clinical treatment of IRI.