Ventricular hypertrophy is an adaptive process wherein an increase in cardiac volume and mass occurs in response to a variety of physiologic and pathologic stimuli. Most common among the latter is pressure overload hypertrophy (POH) consequent to systemic hypertension. Initial chamber remodeling associated with this process permits the left ventricle to favorably adapt to the increased external work by normalizing wall stress. If the abnormal workload persists, alterations in cardiac chamber and muscle properties eventuate in congestive heart failure (CHF) by molecular mechanisms which are poorly understood. The overall hypothesis for this research program is that the transition between compensated pressure overload hypertrophy and congestive heart failure results-from distinctive combinatorial alterations in cardiac hypertrophy triggers, transducers and target proteins intrinsic to the adult cardiomyocyte. The major objective of this project is to develop a small animal model of pressure overload hypertrophy and congestive heart failure to elucidate stage specific molecular and biochemical events which underlie this transition. To test this hypothesis and to achieve this objective, we will examine five Specific Aims: 1) To develop a small animal model which manifests compensated POH (normal myocyte function, normal chamber function, no systemic or pulmonary congestion) and CHF (abnormal myocyte function, depressed chamber function and pulmonary congestion) by descending thoracic aortic banding. 2) To examine the potential differential response in protein synthesis to mechanical deformation of adult cardiomyocytes extracted from ventricles during these two stages; 3) To study the potential role of differential activation of protein kinase C by mechanical stress between compensated POH and CHF; 4) To examine the stretch sensitive transcriptional regulation of P-myosin heavy chain in vivo with variable length beta-MHC promoter sequences hybridized to a CAT reporter gene after POH produced by transverse aortic banding; and 5) To study potential differences in the calcium cycling proteins (SR ATPase, phospholamban, ryanodine receptor, calsequestrin) which may occur between POH and CHF at the steady state mRNA, protein and functional levels and to relate these differences to altered mechanics and intracellular calcium kinetics of the isolated cardiomyocyte and the isolated Langendorff perfused heart.
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