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

ABSTRACT: 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.We studied the molecular mechanism mediating the effect of GSK-3? activation/inhibition upon myocardial injury during prolonged ischemia and I/R.Beta isoform-specific inhibition of GSK-3 by dominant negative GSK-3? in transgenic mice (Tg-DnGSK-3?) or in heterozygous GSK-3? knock-out mice (GSK-3?+/-) significantly increased, whereas activation of GSK-3? in constitutively active GSK-3? knock-in mice (?KI) significantly decreased, myocardial ischemic injury after prolonged ischemia. In contrast, inhibition of GSK-3? in Tg-DnGSK-3? or GSK-3?+/- significantly reduced, while activation of GSK-3? in ?KI significantly enhanced, myocardial I/R injury. Inhibition of GSK-3? 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-3? inhibition on both prolonged ischemic injury and I/R injury. Importantly, the influence of rapamycin over the effects of GSK-3? inhibition on myocardial injury was reversed by inhibition of autophagy.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.

SUBMITTER: Zhai P

PROVIDER: S-EPMC3158807 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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

Zhai Peiyong P Sciarretta Sebastiano S Galeotti Jonathan J Volpe Massimo M Sadoshima Junichi J

Circulation research 20110707 5

<h4>Rationale</h4>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.<h4>Objective</h4>We studied the molecular mechanism mediating the effect of GSK-3β activation/inhibition upon myocardial injury during prolonged ischemia and I/R.<h4>Methods and results</h4>Beta isoform-specific inhibition of GSK-3 by dominant negative ...[more]

PMID: 21737790

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Project description:GsMTx4 is a selective inhibitor of cationic mechanosensitive ion channels (MSCs) and has helped establish the role of MSCs in cardiac physiology. Inhomogeneous local mechanical stresses due to hypercontracture and swelling during ischemic reperfusion injury (IRI) likely induce elevated MSC activity that can contribute to cation imbalance. The aim of this study was to determine if the D enantiomer of GsMTx4 can act as a cardioprotectant in a mouse IRI model. Ischemia and reperfusion involved ligating a coronary artery followed by release of the ligature. GsMTx4-D was tested by either acute intravenous injection during the ischemic event or by two day pretreatment by intraperitoneal injection, both methods achieving similar results. Based on pharmacokinetic studies, GsMTx4-D dosage was set to achieve expected plasma concentrations between 50 and 5000nM and heart tissue concentrations between 1 and 200nM by intravenous injection. Relative to vehicle injected animals, GsMTx4-D reduced infarct area by ~40% for acute and pretreated animals for both 20 and 45min ischemic challenges. Many indicators of cardiac output were indistinguishable from sham-treated control hearts after GsMTx4-D treatment showing improvement at both 4 and 48h post ischemia, and premature ventricular beats immediately following reperfusion were also significantly reduced. To determine if GsMTx4-D cardioprotection could act directly at the level of cardiomyocytes, we tested its effects in vitro on indicators of IRI damage like cation influx and activation of inflammatory kinases in isolated myocytes cultured under hypoxic conditions. Hypoxia challenged cardiomyocytes treated with 10μM GsMTx4-D showed improved contractility and near normal contraction-related Ca(2+) influx. GsMTx4-D inhibited indicators of ischemic damage such as the apoptotic signaling system JNK/c-Jun, but also inhibited the energy response signaling system Akt kinase. We conclude that GsMTx4-D is a potent cardioprotectant in vivo that may act directly on cardiomyocytes and potentially be useful in multidrug strategies to treat IRI.

Dataset Information

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

Publications

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

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