GSK-3beta, a therapeutic target for cardiomyocyte protection

Glycogen synthase kinase-3beta (GSK-3beta) is a multifunctional Ser/Thr kinase that plays important roles in necrosis and apoptosis of cardiomyocytes. A major mechanism of cell necrosis is the opening of the mitochondrial permeability transition pore (mPTP), which consists of multiple protein subunits, including adenine nucleotide translocase (ANT). The threshold for mPTP opening is elevated by phosphorylation of GSK-3beta at Ser9, which reduces activity of this kinase. How inactivation of GSK-3beta suppresses mPTP opening has not been fully understood, but evidence to date suggests that preservation of hexokinase-II in the mPTP complex, inhibition of cyclophilin-D-ANT binding, inhibition of p53 and inhibition of ANT into the mitochondria are contributory. GSK-3beta phosphorylation is a step to which multiple protective signaling pathways converge, and thus GSK-3beta phosphorylation is crucial in cardioprotection of a variety of interventions against ischemia/reperfusion injury. Apoptosis of cardiomyocytes by pressure overload or ischemia/reperfusion is also suppressed by inactivation of GSK-3beta, in which reduced phosphorylation of p53, heat shock factor-1 and myeloid cell leukemia sequence-1 and inhibition of Bax translocation might be involved. Considering predominant roles of GSK-3beta in cardiomyocyte death, manipulation of this protein kinase is a promising strategy for myocardial protection in coronary artery disease and heart failure.