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Ann Thorac Surg 2007;84:126-133
© 2007 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Inhibition of Glycogen Synthase Kinase-3ß Improves Tolerance to Ischemia in Hypertrophied Hearts

Rodrigo Barillas, MD, MBA*, Ingeborg Friehs, MD*, Hung Cao-Danh, PhD, Joseph F. Martinez, DVM, Pedro J. del Nido, MD*

Department of Cardiac Surgery, Children’s Hospital Boston and Harvard Medical School, Boston, Massachusetts

Accepted for publication February 6, 2007.

* Address correspondence to Dr del Nido, Department of Cardiac Surgery, Children’s Hospital Boston, Harvard Medical School, 300 Longwood Ave, Bader 279, Boston, MA 02115 (Email: pedro.delnido{at}cardio.chboston.org).

Background: Hypertrophied myocardium is more susceptible to ischemia/reperfusion injury, in part owing to impaired insulin-mediated glucose uptake. Glycogen synthase kinase-3ß (GSK-3ß) is a key regulatory enzyme in glucose metabolism that, when activated, phosphorylates/inactivates target enzymes of the insulin signaling pathway. Glycogen synthase kinase-3ß is regulated upstream by Akt-1. We sought to determine whether GSK-3ß 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-3ß inhibitor (0.1 mM Li; 1 µM IMI) as cardioplegic additives. Cardiac function was measured before and after ischemia. Expression, activity of Akt-1 and GSK-3ß, and lactate were determined at end-ischemia.

Results: Contractile function after ischemia was better preserved in hypertrophied hearts treated with GSK-3ß inhibitors. Activity of Akt-1 was significantly impaired in hypertrophied myocardium at end-ischemia. Glycogen synthase kinase-3ß 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-3ß by Akt-1 in hypertrophied hearts is impaired, leading to activation during ischemia. Inhibition of GSK-3ß 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.


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