Research Project
6527468
Postnatal mammalian cardiomyocytes respond to mechanical stress, growth factor and hormonal action, and metabolic abnormalities by enlarging, but these cells are unable to proliferate for reasons that are not understood. The clinical consequences of human cardiac hypertrophy are very significant and include the development of serious cardiac arrhythmias, of diastolic dysfunction that can result in pulmonary edema and fluid overload, and of congestive heart failure. Intracellular signaling cascades play a major role in the development of cardiac hypertrophy. Several lines of evidence support the role of G proteins in the development of cardiac hypertrophy. RGS (regulator of G protein signaling) proteins were recently found to be GTPase activating proteins (GAPs) for heterotrimeric G proteins. In this proposal, we will outline experiments to test the hypothesis that RGS proteins determine the responsiveness of cardiomyocytes to extracellular stimuli, and that RGS gene expression can be increased as an adaptive mechanism to limit G- protein-mediated signal transduction. We will examine the expression pattern of RGS family members in animal models of cardiac hypertrophy and congestive heart failure. We will determine the relative ability of RGS family members to block cardiomyocyte signal transduction and hypertrophic growth. We will determine whether RGS4 inhibits cardiac hypertrophy in a transgenic mouse model in response to provocative stimuli. Finally, we will determine whether dominant negative mutant forms of RGS2 and RGS4 promote cardiomyocyte signal transduction and hypertrophic growth. These experiments will help to establish the role of RGS proteins in the pathophysiology of cardiac hypertrophy and may have an impact on future treatment of patients with this disorder and those in whom hypertrophy has progressed to heart failure.
