ENHANCED G-ALPHA-Q SIGNALING - A COMMON PATHWAY MEDIATES CARDIAC-HYPERTROPHY AND APOPTOTIC HEART-FAILURE

Receptor-mediated Gq signaling promotes hypertrophic growth of culture d neonatal rat cardiac myocytes and is postulated to transduce in vivo cardiac pressure overload hypertrophy, Although initially compensator y, hypertrophy can proceed by unknown mechanisms to cardiac failure. W e used adenoviral infection and transgenic overexpression of the alpha subunit of Gq to autonomously activate Gq signaling in cardiomyocytes . In cultured cardiac myocytes, overexpression of wild-type G alpha q resulted in hypertrophic growth. Strikingly, expression of a constitut ively activated mutant of G alpha q, which further increased Gq signal ing, produced initial hypertrophy, which rapidly progressed to apoptot ic cardiomyocyte death. This paradigm was recapitulated during pregnan cy in G alpha q overexpressing mice and in transgenic mice expressing high levels of wild-type G alpha q. The consequence of cardiomyocyte a poptosis was a transition from compensated hypertrophy to a rapidly pr ogressive and lethal cardiomyopathy, Progression from hypertrophy to a poptosis irt vitro and in vivo was coincident with activation of p38 a nd Jun kinases, These data suggest a mechanism in which moderate level s of Gq signaling stimulate cardiac hypertrophy whereas high level Go activation results in cardiomyocyte apoptosis, The identification of a single biochemical stimulus regulating cardiomyocyte growth and death suggests a plausible mechanism for the progression of compensated hyp ertrophy to decompensated heart failure.