mTOR Signaling and Cardioprotection in Diabetes

Deregulation of mammalian target of rapamycin (mTOR) signaling has been implicated in many human diseases, including cancer, obesity, diabetes and cardiovascular diseases. We have previously reported that pharmacological inhibition of mTOR with rapamycin exerts preconditioning-like effect in the murine heart through activation of JAK-STAT3 signaling. Reperfusion therapy with rapamycin also protects the murine heart against ischemia/reperfusion injury by selective activation of mTORC2 and ERK with concomitant inhibition of mTORC1 and p38. A persistent hyper activation of mTORC1 has been implicated in obesity-related metabolic pathologies. Chronic treatment with rapamycin improves metabolic status and prevents cardiac dysfunction in type 2 diabetic mice through attenuation of oxidative stress as well as alteration of contractile and glucose metabolic proteins. Rapamycin treatment at reperfusion also preserves cardiac function with reduction of myocardial infarction in diabetic mice through STAT3 signaling. In alloxan-treated type-I diabetic rabbits, rapamycin treatment at the onset of reperfusion reduced myocardial infarction with reduction of cardiac troponin I level in blood as compared to control. Rapamycin significantly reduced apoptosis in the peri-infarct region with restoration of Bcl2/Bax ratio. Cardiac microRNA-302a, a regulator of anti-apoptosis through activating AKT signaling, was reduced after ischemia/reperfusion in diabetic rabbits, but restored with rapamycin treatment. PTEN, a target of miR-302a, was increased after ischemia/reperfusion, which was inhibited by rapamycin. Rapamycin specifically inhibited diabetes-induced phosphorylation of S6 (marker of mTORC1 activation), but restored AKT (marker of mTORC2). Therefore, selective targeting of mTOR subcomplexes may hold therapeutic promise to combat myocardial infarction and improve prognosis in diabetic patients.