Hydrogen sulfide protects cardiomyocytes from hypoxia/reoxygenation-induced apoptosis by preventing GSK-3β-dependent opening of mPTP

Yao LL, Huang XW, Wang YG, Cao YX, Zhang CC, Zhu YC. Hydrogen sulfide protects cardiomyocytes from hypoxia/reoxygenation-induced apoptosis by preventing GSK-3 beta-dependent opening of mPTP. Am J Physiol Heart Circ Physiol 298: H1310-H1319, 2010. First published February 12, 2010; doi:10.1152/ajpheart.00339.2009.-Hydrogen sulfide (H2S) is an endogenously generated gaseous transmitter, which has recently been suggested to regulate cardiovascular functions. The present study aims to clarify the mechanisms underlying the cardioprotective effects of H2S. Signaling elements were examined in cardiomyocytes cultured under hypoxia/reoxygenation conditions and in a rat model of ischemia-reperfusion. In cultured cardiomyocytes, sodium hydrosulfide (NaHS; 10, 30, and 50 mu mol/l) showed concentration-dependent inhibitory effects on cardiomyocyte apoptosis induced by hypoxia/reoxygenation. These effects were associated with an increase in phosphorylation of glycogen synthase kinase-3 beta (GSK-3 beta) (Ser9) and a decrease in Bax translocation, caspase-3 activation, and mitochondrial permeability transition pore (mPTP) opening. Transfection of a phosphorylation-resistant mutant of GSK-3 beta at Ser9 attenuated the effects of NaHS in reducing cardiomyocyte apoptosis, Bax translocation, caspase-3 activation, and mPTP opening. In a rat model of ischemia-reperfusion, NaHS administration reduced myocardial infarct size and increased the phosphorylation of GSK-3 beta (Ser9) at a dose of 30 mu mol/kg. In conclusion, the H2S donor prevents cardiomyocyte apoptosis by inducing phosphorylation of GSK-3 beta (Ser9) and subsequent inhibition of mPTP opening.