The mechanisms responsible for the transition from stable compensated hypertrophy to myocardial dysfunction are not well understood. Several hypotheses have been suggested to be responsible for the progression of myocardial dysfunction including: alterations in Ca++ availability, abnormalities in the myocyte cytoskeleton such as microtubular polymerization, decreased volume fraction of cardiomyocyte myofibrils, and aberrations in beta-adrenergic receptor (beta-AR) signaling. In this regard, an important characteristic of human heart failure is diminished beta-AR number (receptor down regulation) and impaired beta-AR function (receptor uncoupling). Recent data suggest a step-wise increase in plasma norepinephrine levels in individuals from normal to asymptomatic left ventricular (LV) dysfunction and to symptomatic LV failure. Thus high levels of circulating catecholamines early in the transition from stable cardiac hypertrophy to Lv dysfunction, may account, in part, for the observed loss in beta-AR function. it therefore becomes apparent that abnormalities in beta-AR signaling are potential key targets, that if corrected, may interrupt the gradual deterioration of myocardial function in the clinical course of heart failure. The overall goal of this project is to use mouse genetics to specifically inhibit betaARK or to chronically enhance myocyte contractility during the transition from stable hypertrophy to decompensated dilated cardiomyopathy followed by a comprehensive biochemical, molecular and physiological analysis of beta-AR signaling and cardiac function. Studies are proposed to test the hypothesis that beta-adrenergic receptor desensitization early in the time course of a cardiomyopathy contributes to the progressive deterioration in contractile function, and that correction of the gene defect using mouse genetics can modify or even ameliorate the disease phenotype.
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