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

作者：Zhai Peiyong; Sciarretta Sebastiano; Galeotti Jonathan; Volpe Massimo; Sadoshima Junichi^*

来源：Circulation Research, 2011, 109(5): 502-U123.

DOI：10.1161/CIRCRESAHA.111.249532

• ischemia
• reperfusion
• apoptosis
• autophagy
• GSK-3
• Beclin 1
• rapamycin
• mTOR

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 beta 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 beta in transgenic mice (Tg-DnGSK-3 beta) or in heterozygous GSK-3 beta knock-out mice (GSK-3 beta+/-) significantly increased, whereas activation of GSK-3 beta in constitutively active GSK-3 beta knock-in mice (beta KI) significantly decreased, myocardial ischemic injury after prolonged ischemia. In contrast, inhibition of GSK-3 beta in Tg-DnGSK-3 beta or GSK-3 beta+/- significantly reduced, while activation of GSK-3 beta in beta KI significantly enhanced, myocardial I/R injury. Inhibition of GSK-3 beta stimulated mTOR signaling and inhibited autophagy through a rapamycinsensitive (mTOR dependent) mechanism. Rapamycin enhanced autophagy and, at the same time, abolished the effects of GSK-3 beta inhibition on both prolonged ischemic injury and I/R injury. Importantly, the influence of rapamycin over the effects of GSK-3 beta 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. (Circ Res. 2011; 109: 502-511.)

• 出版日期2011-8-19