Differential Roles of GSK-3 During Myocardial Ischemia and Ischemia/Reperfusion

Rationale: Inhibition of glycogen synthase kinase-3 (GSK-3) protects the heart during ischemia/reperfusion (I/R), yet the underlying mechanisms of cardioprotection afforded by beta isoform-specific inhibition GSK-3 remain to be elucidated. Objective: We studied the molecular mechanism mediating the effect of GSK-3 activation/inhibition upon myocardial injury during prolonged ischemia and I/R. Methods and Results: Beta isoform–specific inhibition of GSK-3 by dominant negative GSK-3 in transgenic mice (Tg-DnGSK-3) or in heterozygous GSK-3 knock-out mice (GSK-3/) significantly increased, whereas activation of GSK-3 in constitutively active GSK-3 knock-in mice (KI) significantly decreased, myocardial ischemic injury after prolonged ischemia. In contrast, inhibition of GSK-3 in Tg-DnGSK-3 or GSK-3/ significantly reduced, while activation of GSK-3 in KI significantly enhanced, myocardial I/R injury. Inhibition of GSK-3 stimulated mTOR signaling and inhibited autophagy through a rapamycin-sensitive (mTOR dependent) mechanism. Rapamycin enhanced autophagy and, at the same time, abolished the effects of GSK-3 inhibition on both prolonged ischemic injury and I/R injury. Importantly, the influence of rapamycin over the effects of GSK-3 inhibition on myocardial injury was reversed by inhibition of autophagy. Conclusions: Our results suggest that beta isoform–specific inhibition of GSK-3 exacerbates ischemic injury bu