RRC ID 27889
Author Zhai P, Sciarretta S, Galeotti J, Volpe M, Sadoshima J.
Title Differential roles of GSK-3β during myocardial ischemia and ischemia/reperfusion.
Journal Circ Res
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.
Volume 109(5)
Pages 502-11
Published 2011-8-19
DOI 10.1161/CIRCRESAHA.111.249532
PMID 21737790
PMC PMC3158807
MeSH Animals Autophagy / genetics Gene Knock-In Techniques / methods Glycogen Synthase Kinase 3 / genetics Glycogen Synthase Kinase 3 / physiology* Glycogen Synthase Kinase 3 beta Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Myocardial Ischemia / enzymology* Myocardial Ischemia / pathology Myocardial Reperfusion Injury / enzymology* Myocardial Reperfusion Injury / pathology Signal Transduction / genetics TOR Serine-Threonine Kinases / genetics TOR Serine-Threonine Kinases / metabolism TOR Serine-Threonine Kinases / physiology
IF 14.467
Times Cited 114
Mice RBRC00806