Cardiac hypertrophy is the response of the myocardium to both physical and metabolic stress. Hypertrophy triggered by acute hemodynamic overload and hypertension elicit specific modulations in expression of essential myocardial proteins and a concomitant decrease in contractibility per unit of myocardium. It is not clear to what extent the anomalous expression of these proteins contribute to the altered contractile performance during hypertrophy and the onset of heart failure. Identification and characterization of cellular and sub-cellar processes that control the biosynthesis and function of muscle proteins is the key to understanding the pathogenesis of this cardiac disorder. The observations that expression of eukaryotic genes is mediated by nuclear regulatory factors which participate in active transcription complex formation taken together with the evidence that hemodynamic overload causes altered gene expression provides a framework in which to test whether modulations in tissue specific regulatory factors occur in response to signals associated with hypertrophy. There are two basis objectives outlined in this proposal: first, to establish that specific alterations in the composition of regulatory factors are responsible for activation (or repression) of a candidate gene, such as, for myosin light chain (MLC2), which appears to biochemically characterize the cardiac hypertrophic process; second, to investigate the contribution of MLC2 isotype in function adaption of the myocardium during hypertrophy. The first objective will be accomplished by identifying MLC2 specific regulatory factors which response to hemodynamic overload and characterizing in detail their role in altered expression of proteins in hypertrophied heart muscle. Towards the second objective, we shall produce variant MLC2 isotypes, with defined mutations in the putative functional domain of the polypeptide, and substitute these variants for the native protein in order to explore the structural requirements for MLC2 function in the reconstituted actomyosin complex. The accomplishment of these objectives will define the mechanism(s) by which cardiac workload leads to anomalous production of myocardial proteins and to altered mechanical performance of the heart muscle.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Pulmonary Research A Study Section (CVA)
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Suny Downstate Medical Center
Schools of Medicine
United States
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