Testosterone induces cytoprotection by activating ATP-sensitive K + channels in the cardiac mitochondrial inner membrane

Abstract

Background - Whereas in the past, androgens were mainly believed to exert adverse effects on the cardiovascular system, recent experimental data postulate a benefit of testosterone for recovery of myocardial function after ischemia/ reperfusion injury. Thus, we examined whether testosterone might improve myocardial tolerance to ischemia due to activation of mitochondrial (mitoK ATP) and/or sarcoplasmatic (sarcKATP) KATP channels. Methods and Results - In a cellular model of ischemia, testosterone significantly decreased the rate of ischemia-induced death of cardiomyocytes that could be prevented by 5-hydroxydecainoic acid but was unaffected by the sarcKATP blocker HMR1098 and the testosterone receptor antagonist flutamide. To index mitoKATP, mitochondrial flavoprotein fluorescence was measured. Testosterone induced a highly significant increase in mitochondrial flavoprotein fluorescence in intact myocytes and isolated mitoplasts that could be abolished by 5-hydroxydecainoic acid. Testosterone-mediated flavoprotein oxidation of mitoplasts was K+ dependent and ATP sensitive. In mitoplast-attached single-channel recordings, testosterone directly activated an ATP-sensitive K+ channel of the inner mitochondrial membrane. Addition of the KATP channel opener diazoxide and pinacidil to the cytosolic solution activated the ATP-sensitive K+ current comparable to testosterone, whereas 5-hydroxydecainoic acid and glibenclamide inhibited the testosterone-induced current. Patch-clamp experiments of intact myocytes in whole-cell configuration did not demonstrate any effect of testosterone on sarcKATP channels. Conclusions - Our results provide direct evidence for the existence of cardiac mitoKATP and a link between testosterone-induced cytoprotection and activation of mitoKATP. Endogenous testosterone might play a more important role in recovery after myocardial infarction than is currently assumed.