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

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Original Articles: Cardiovascular

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

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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Invited commentary

David J. Chambers
Ann. Thorac. Surg. 2007 84: 133. [Extract] [Full Text] [PDF]

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				J. R. Bell, E. R. Porrello, C. E. Huggins, S. B. Harrap, and L. M. D. Delbridge The intrinsic resistance of female hearts to an ischemic insult is abrogated in primary cardiac hypertrophy Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1514 - H1522. [Abstract] [Full Text] [PDF]

				D. J. Chambers Invited commentary Ann. Thorac. Surg., July 1, 2007; 84(1): 133 - 133. [Full Text] [PDF]