Energy substrate utilization is altered in hypertrophied and failing hearts. Specifically, hypertrophied hearts show increases in basal glucose uptake and glycolysis, associated with decreases in fatty acid oxidation, suggesting a shift of substrate preference in these hearts. One key player for energy substrate switch in the heart is peroxisome proliferator activated receptor alpha (PPAR alpha), a nuclear receptor that regulates expressions of multiple genes controlling fatty acid metabolism. Down-regulation of PPAR alpha, widely observed in cardiac hypertrophy, allows shifting substrate preference from fatty acid to glucose; and was thought to be a necessary adaptation in hypertrophied hearts. Down-regulation of PPAR alpha alone, however, does not prevent the development of heart failure, and decreases in the protein or activity of enzymes encoded by PPAR alpha parallel the transition from compensated hypertrophy to failure. Thus, the functional significance of substrate switch remains incompletely understood. In the previous funding period, we generated transgenic mice with cardiac-specific overexpression of insulin-independent glucose transporter GLUT1 (TG). The TG hearts have successfully recapitulated the increases in glucose uptake and glycolysis observed in hypertrophied hearts but at a substantially higher level. Using this model, we have made the exciting observation that increasing glucose transport protects against the development of heart failure and improves the survival in mice with ascending aortic constriction. The goal of this application is to determine why chronic increases in glucose uptake prevent the development of heart failure and to test potential therapeutic approaches. Our central hypothesis is that the benefit of increasing glucose uptake in hypertrophied hearts derives from increases both in glycolysis and glucose oxidation: Increased glycolytic ATP production supports sarcoplasmic reticulum Ca2+-ATPase (SERCA) during chronic hemodynamic overload and increased glucose oxidation enhance the substrate shift initiated by the down-regulation of PPAR alpha and thereby achieving an adaptive energy metabolism in hypertrophied hearts.
Our specific aims are test the following hypotheses: 1) further enhancing glucose transport in hearts with down-regulation of PPAR alpha is necessary to establish an adaptive substrate oxidation profile for high workload. 2) increasing ATP generation via glycolysis improves SERCA function and maintains Ca 2. homeostasis in hypertrophied cardiac myocytes. 3) increasing glucose transport in failing hearts improves energy supply and contractile performance. 4) increasing glucose transport enhances the efficacy of SERCA2a overexpression in the treatment of heart failure. ? ?
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