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

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.

• Authors: Peiyong Zhai, Sebastiano Sciarretta, Jonathan Galeotti, Massimo Volpe, Junichi Sadoshima
• Journal: Circulation research (Circ Res) Vol. 109 Issue 5 Pg. 502-11 (Aug 19 2011) ISSN: 1524-4571 [Electronic] United States
• PMID: 21737790 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• mTOR protein, mouse
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• TOR Serine-Threonine Kinases
• Glycogen Synthase Kinase 3

Topics

• Animals
• Autophagy (genetics)
• Gene Knock-In Techniques (methods)
• Glycogen Synthase Kinase 3 (genetics, physiology)
• Glycogen Synthase Kinase 3 beta
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Myocardial Ischemia (enzymology, pathology)
• Myocardial Reperfusion Injury (enzymology, pathology)
• Signal Transduction (genetics)
• TOR Serine-Threonine Kinases (genetics, metabolism, physiology)