After two decades of study, we have come to realize that for prevention and treatment of heart failure, it is essential to understand the mechanisms underlying the development of cardiac hypertrophy which proceed to heart failure, and to identify factors which contribute to the transition to heart failure. The glycolytic pathway is an essential component of the molecular machinery of the cell. Alterations in the enzyme activity and substrate contents for enzymes in glycolysis have been observed in numerous animal models of cardiac hypertrophy and heart failure, as well as in failing human myocardium. Their functional significance and importantly, their roles in the development of heart failure have yet to be defined. The goal of this research project is to fill in this significant gap and to define the role of altered glucose utilization in the pathogenesis of cardiac hypertrophy and transition to heart failure. Taking advantage of an established model of pressure overload hypertrophy, namely rats with banded ascending aorta, we will perform a longitudinal study to cover the full spectrum of cardiac pathology from hypertrophy to failure. Using a combination of the tools of physiology, biochemistry, biophysics, and molecular biology, we will determine the time course of and the mechanisms which determine the alterations in glucose entry and in vivo regulation of phosphofructokinase (PFK) activity, as well as their significance for contractile function in hearts with hypertrophy and failure. Knowledge gained from this study will not only enhance our understanding of this metabolic pathway in cardiac hypertrophy but could also shape future strategies for the prevention and treatment of heart failure.
The specific aims are: To test the hypothesis that the balance between basal and insulin-regulated glucose entry shifts in cardiac hypertrophy and failure, specifically, that there is a progressive increase in basal glucose entry during the evolution of heart failure. To test the hypothesis that glycolysis is activated in the hypertrophied heart via the activation of PFK and cannot be activated further in the failing heart. To test the hypothesis that increase glucose utilization in hypertrophied heart, as a compensatory mechanism, has reached its maximum and is not able to increase further to support ATP synthesis and the recruitment of contractile reserve in the failing heart.
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