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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, METHODS, RESULTS. Meshes: Animals, Body Weight, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Glycolysis, Hypertrophy, Left Ventricular, Indoles, Lactic Acid, Lithium Compounds, Myocardial Contraction, Myocardial Ischemia, Myocardial Reperfusion Injury, Oximes, Phosphorylation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Rabbits.
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Does inhibition of glycogen synthase kinase-3beta improve tolerance to ischemia in hypertrophied hearts? Context: 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. 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. 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.
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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. Final Decision: yes