Inhibition of glycogen synthase kinase-3β improves tolerance to ischemia in hypertrophied hearts

Background. Hypertrophied myocardium is more susceptible to ischemia/reperfusion injury, in part owing to impaired insulin-mediated glucose uptake. Glycogen synthase kinase-3 beta (GSK-3 beta) is a key regulatory enzyme in glucose metabolism that, when activated, phosphorylates/ inactivates target enzymes of the insulin signaling pathway. Glycogen synthase kinase-3 beta is regulated upstream by Akt-1. We sought to determine whether GSK-3 beta 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-3 beta inhibitor (0.1 mM Li; 1 mu M IMI) as cardioplegic additives. Cardiac function was measured before and after ischemia. Expression, activity of Akt-1 and GSK-3 beta, and lactate were determined at end-ischemia. Results. Contractile function after ischemia was better preserved in hypertrophied hearts treated with GSK-3 beta inhibitors. Activity of Akt-1 was significantly impaired in hypertrophied myocardium at end-ischemia. Glycogen synthase kinase-3 beta 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-3 beta by Akt-1 in hypertrophied hearts is impaired, leading to activation during ischemia. Inhibition of GSK-3 beta 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.