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Circ Res. 2011 Aug 19;109(5):502-11. doi: 10.1161/CIRCRESAHA.111.249532. Epub 2011 Jul 7.

Differential roles of GSK-3β during myocardial ischemia and ischemia/reperfusion.

Author information

1
Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.

Abstract

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-3β 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-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.

PMID:
21737790
PMCID:
PMC3158807
DOI:
10.1161/CIRCRESAHA.111.249532
[Indexed for MEDLINE]
Free PMC Article

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