Loss of PI3K Mediates Protection From Myocardial Ischemia-Reperfusion Injury Linked to Preserved Mitochondrial Function

BackgroundIdentifying new therapeutic targets for preventing the myocardial ischemia-reperfusion injury would have profound implications in cardiovascular medicine. Myocardial ischemia-reperfusion injury remains a major clinical burden in patients with coronary artery disease. Methods and ResultsWe studied several key mechanistic pathways known to mediate cardioprotection in myocardial ischemia-reperfusion in 2 independent genetic models with reduced cardiac phosphoinositide 3-kinase-& alpha; (PI3K & alpha;) activity. P3K & alpha;-deficient genetic models (PI3K & alpha;DN and PI3K & alpha;-Mer-Cre-Mer) showed profound resistance to myocardial ischemia-reperfusion injury. In an ex vivo reperfusion protocol, PI3K & alpha;-deficient hearts had an 80% recovery of function compared with & AP;10% recovery in the wild-type. Using an in vivo reperfusion protocol, PI3K & alpha;-deficient hearts showed a 40% reduction in infarct size compared with wild-type hearts. Lack of PI3K & alpha; increased late Na+ current, generating an influx of Na+, facilitating the lowering of mitochondrial Ca2+, thereby maintaining mitochondrial membrane potential and oxidative phosphorylation. Consistent with these functional differences, mitochondrial structure in PI3K & alpha;-deficient hearts was preserved following ischemia-reperfusion injury. Computer modeling predicted that PIP3, the product of PI3K & alpha; action, can interact with the murine and human Na(V)1.5 channels binding to the hydrophobic pocket below the selectivity filter and occluding the channel. ConclusionsLoss of PI3K & alpha; protects from global ischemic-reperfusion injury linked to improved mitochondrial structure and function associated with increased late Na+ current. Our results strongly support enhancement of mitochondrial function as a therapeutic strategy to minimize ischemia-reperfusion injury.