Differential Roles of GSK-3β During Myocardial Ischemia and Ischemia/Reperfusion
Background: Inhibition of glycogen synthase kinase-3 (GSK-3) protects the heart during ischemia/reperfusion (I/R). However, the underlying mechanisms of cardioprotection afforded by beta isoform–specific inhibition of GSK-3 remain to be elucidated.
Methods and Results: We studied the molecular mechanism mediating the effect of GSK-3β activation/inhibition on myocardial injury during prolonged ischemia and I/R. Beta isoform–specific inhibition of GSK-3 by dominant negative GSK-3β in transgenic mice (Tg-DnGSK-3β) or in heterozygous GSK-3β knock-out mice (GSK-3β±) significantly increased, whereas activation of GSK-3β in constitutively active GSK-3β knock-in mice (βKI) significantly decreased, myocardial ischemic injury after prolonged ischemia. In contrast, inhibition of GSK-3β in Tg-DnGSK-3β or GSK-3β± significantly reduced, while activation of GSK-3β in βKI significantly enhanced, myocardial I/R injury. Inhibition of GSK-3β 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-3β inhibition on both prolonged ischemic injury and I/R injury. Importantly, the influence of rapamycin over the effects of GSK-3β 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 but protects against I/R injury by modulating mTOR and autophagy.
- Received May 27, 2011.
- Revision received June 22, 2011.
- Accepted June 24, 2011.
- © 2011 American Heart Association, Inc.