Enhanced recovery from ischemia-reperfusion injury in PI3K alpha dominant negative hearts: Investigating the role of alternate PI3K isoforms, increased glucose oxidation and MAPK signaling

Classical ischemia-reperfusion (IR) preconditioning relies on phosphatidylinositol 3-kinase (PI3K) for protective signaling. Surprisingly, inhibition of PI3K alpha activity using a dominant negative (DN) strategy protected the murine heart from IR injury. It has been proposed that increased signaling through PI3K gamma may contribute to the improved recovery of PI3K alpha DN hearts following IR. To investigate the mechanism by which PI3K alpha DN hearts are protected from IR injury, we created a double mutant (PI3KDM) model by crossing p110 gamma(-/-) (PI3K gamma KO) with cardiac-specific PI3K alpha DN mice. The PI3KDM model has morphological and hemodynamic features that are characteristic of both PI3K gamma(-/-) and PI3K alpha DN mice. Interestingly, when subjected to IR using ex vivo Langendorff perfusion, PI3KDM hearts showed significantly enhanced functional recovery when compared to wildtype (WT) hearts. However, signaling downstream of PI3K through Akt and GSK3 beta, which has been associated with IR protection, was reduced in PI3KDM hearts. Using ex vivo working heart perfusion, we found no difference in functional recovery after IR between PI3KDM and PI3K alpha DN; also, glucose oxidation rates were significantly increased in PI3K alpha DN hearts when compared to WT, and this metabolic shift has been associated with enhanced IR recovery. However, we found that PI3K alpha DN hearts still had enhanced recovery when perfused exclusively with fatty acids (FA). We then investigated parallel signaling pathways, and found that mitogen-activated protein kinase signaling was increased in PI3K alpha DN hearts, possibly through the inhibition of negative feedback loops downstream of PI3K alpha. (c) 2012 Elsevier Ltd. All rights reserved.