Extracellular PKM2 Preserves Cardiomyocytes and Reduces Cardiac Fibrosis During Myocardial Infarction

Substantial loss of cardiomyocytes during heart attacks and onset of other cardiovascular diseases is a major cause of mortality. Preservation of cardiomyocytes during cardiac injury would be the most effective strategy to manage these diseases in clinic. However, there is no effective treatment strategy that is able to prevent cardiomyocyte loss. We demonstrate here that the systemic administration of a recombinant PKM2 mutant (G415R) preserves cardiomyocytes and reduces cardiac fibrosis during myocardial infarction. G415R preserves cardiomyocytes by protecting the cardiomyocytes from dying and by promoting cardiomyocyte proliferation. Preservation of cardiomyocytes by extracellular PKM2 (EcPKM2) reduces cardiac fibrosis because of the decreased activation of cardiac fibroblasts. Our experiments show that EcPKM2 (G415R) exerts its action by interacting with integrin a_vb₃ on cardiomyocytes. EcPKM2(G415R) activates the integrin-FAK-PI3K signaling axis, which subsequently suppresses PTEN expression and consequently regulates cardiomyocyte apoptosis resistance and proliferation under hypoxia and oxidative stress conditions. Our studies uncover an important cardiomyocyte protection mechanism. More importantly, the activity/action of EcPKM2 (G415R) in preserving cardiomyocyte suggesting a possible therapeutic strategy and target for the treatment of heart attacks and other cardiovascular diseases.