Myocardial hypertrophy remains an important risk factor for pediatric cardiac surgery of congenital and acquired heart disease. Clinical and experimental studies have shown that hypertrophied myocardium exhibits a worse recovery of contractile function post-ischemia. Glucose transport/utilization by myocytes is critical for normal function, and during ischemia and early reperfusion. Exogenous glucose for glycolysis enters the cell via a transporter protein (GLUT-1 and 4 in the heart), and at physiologic glucose concentrations, glucose entry into the cell is rate-limiting for its subsequent metabolism. Using a model of pressure overload hypertrophy (aortic banding at 10 days of age), we have shown that in hypertrophied hearts, glucose transport across the sarcolemma in response to insulin is impaired and this change is associated with worse recovery after ischemic injury. Inversely, improving glucose uptake significantly improves post-ischemic recovery in hypertrophied hearts. We therefore hypothesize that impaired glucose transport into myocytes is in large part responsible for the decreased tolerance of hypertrophied myocardium to ischemia. Insulin insensitivity, with resultant lack of activation of glucose transporters and downregulation of glucose transporter expression occurs in conjunction with the development of uncompensated hypertrophy. Proteins such as tumor necrosis factor which are elevated in congestive heart failure, can inhibit insulin response and cause downregulation of glucose transporters in myocytes. The overall goal of this project is to increase our understanding of the role and mechanism responsible for decreased glucose uptake in hypertrophied myocardium and to develop novel therapies to improve tolerance to ischemia. The P.I. has brought together a multidisciplinary group of investigators with expertise in the various aspects of the project. We will pursue three specific aims to determine the mechanism responsible for insulin insensitivity in the hypertrophied heart (AIM I); test the efficacy of interventions aimed at bypassing the functional defect in insulin signaling (AIM II); and determine the effect and mechanism of action of tumor necrosis on glucose uptake and glucose transporter expression in cardiac myocytes in culture (AIM III). We will use a model of pressure overload hypertrophy generated by aortic banding of neonatal rabbits. Non-invasive assessment of LV muscle mass with trans-thoracic echocardiography will be used to monitor the development of hypertrophy and progression to heart failure. The hearts will be studied after the development of moderate and severe hypertrophy in an isolated blood perfused heart preparation. We will also perform studies using cardiomyocytes in culture to determine the mechanism responsible for glucose transporter downregulation.
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