BACKGROUND: Hypertrophied myocardium is more susceptible to ischemia/reperfusion injury, in part owing to impaired insulin-mediated glucose uptake. Glycogen synthase kinase-3beta (GSK-3beta) is a key regulatory enzyme in glucose metabolism that, when activated, phosphorylates/inactivates target enzymes of the insulin signaling pathway. Glycogen synthase kinase-3beta is regulated upstream by Akt-1. We sought to determine whether GSK-3beta is activated in ischemic hypertrophied myocardium owing to impaired Akt-1 function, and whether inhibition with lithium (Li) or indirubin-3'-monoxime,5-iodo- (IMI), a specific inhibitor, improves post-ischemic myocardial recovery by improving glucose metabolism. METHODS: Pressure-overload hypertrophy was achieved by aortic banding in neonatal rabbits. At 6 weeks, isolated hypertrophied hearts underwent 30 minutes of normothermic ischemia and reperfusion with or without a GSK-3beta inhibitor (0.1 mM Li; 1 microM IMI) as cardioplegic additives. Cardiac function was measured before and after ischemia. Expression, activity of Akt-1 and GSK-3beta, and lactate were determined at end-ischemia. RESULTS: Contractile function after ischemia was better preserved in hypertrophied hearts treated with GSK-3beta inhibitors. Activity of Akt-1 was significantly impaired in hypertrophied myocardium at end-ischemia. Glycogen synthase kinase-3beta enzymatic activity at end-ischemia was increased in hypertrophied hearts and was blocked by Li or IMI concomitant with significantly increased lactate production, indicating increased glycolysis. CONCLUSIONS: Regulatory inhibition of GSK-3beta by Akt-1 in hypertrophied hearts is impaired, leading to activation during ischemia. Inhibition of GSK-3beta by Li or IMI improves tolerance to ischemia/reperfusion injury in hypertrophied myocardium. The likely protective mechanism is an increase in insulin-mediated glucose uptake, resulting in greater substrate availability for glycolysis during ischemia and early reperfusion.
BACKGROUND:Hypertrophied myocardium is more susceptible to ischemia/reperfusion injury, in part owing to impaired insulin-mediated glucose uptake. Glycogen synthase kinase-3beta (GSK-3beta) is a key regulatory enzyme in glucose metabolism that, when activated, phosphorylates/inactivates target enzymes of the insulin signaling pathway. Glycogen synthase kinase-3beta is regulated upstream by Akt-1. We sought to determine whether GSK-3beta is activated in ischemic hypertrophied myocardium owing to impaired Akt-1 function, and whether inhibition with lithium (Li) or indirubin-3'-monoxime,5-iodo- (IMI), a specific inhibitor, improves post-ischemic myocardial recovery by improving glucose metabolism. METHODS: Pressure-overload hypertrophy was achieved by aortic banding in neonatal rabbits. At 6 weeks, isolated hypertrophied hearts underwent 30 minutes of normothermic ischemia and reperfusion with or without a GSK-3beta inhibitor (0.1 mM Li; 1 microM IMI) as cardioplegic additives. Cardiac function was measured before and after ischemia. Expression, activity of Akt-1 and GSK-3beta, and lactate were determined at end-ischemia. RESULTS: Contractile function after ischemia was better preserved in hypertrophied hearts treated with GSK-3beta inhibitors. Activity of Akt-1 was significantly impaired in hypertrophied myocardium at end-ischemia. Glycogen synthase kinase-3beta enzymatic activity at end-ischemia was increased in hypertrophied hearts and was blocked by Li or IMI concomitant with significantly increased lactate production, indicating increased glycolysis. CONCLUSIONS: Regulatory inhibition of GSK-3beta by Akt-1 in hypertrophied hearts is impaired, leading to activation during ischemia. Inhibition of GSK-3beta by Li or IMI improves tolerance to ischemia/reperfusion injury in hypertrophied myocardium. The likely protective mechanism is an increase in insulin-mediated glucose uptake, resulting in greater substrate availability for glycolysis during ischemia and early reperfusion.
Authors: C Beauloye; L Bertrand; U Krause; A S Marsin; T Dresselaers; F Vanstapel; J L Vanoverschelde; L Hue Journal: Circ Res Date: 2001-03-16 Impact factor: 17.367
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Authors: I Friehs; A M Moran; C Stamm; S D Colan; K Takeuchi; H Cao-Danh; C M Rader; F X McGowan; P J del Nido Journal: Circulation Date: 1999-11-09 Impact factor: 29.690
Authors: S Leclerc; M Garnier; R Hoessel; D Marko; J A Bibb; G L Snyder; P Greengard; J Biernat; Y Z Wu; E M Mandelkow; G Eisenbrand; L Meijer Journal: J Biol Chem Date: 2001-01-05 Impact factor: 5.157
Authors: Waleed G T Masoud; Osama Abo Al-Rob; Yang Yang; Gary D Lopaschuk; Alexander S Clanachan Journal: Cardiovasc Res Date: 2015-07-06 Impact factor: 10.787