Enhanced Gαq signaling: A common pathway mediates cardiac hypertrophy and apoptotic heart failure

John W. Adams, Yoshihito Sakata, Michael G. Davis, Valerie P. Sah, Yibin Wang, Stephen B. Liggett, Kenneth R. Chien, Joan Heller Brown, Gerald W. Dorn

Research output: Contribution to journalArticlepeer-review

451 Scopus citations

Abstract

Receptor-mediated Gq signaling promotes hypertrophic growth of cultured neonatal rat cardiac myocytes and is postulated to transduce in vivo cardiac pressure overload hypertrophy. Although initially compensatory, hypertrophy can proceed by unknown mechanisms to cardiac failure. We 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 Gαq resulted in hypertrophic growth. Strikingly, expression of a constitutively activated mutant of Gαq, which further increased Gq signaling, produced initial hypertrophy, which rapidly progressed to apoptotic cardiomyocyte death. This paradigm was recapitulated during pregnancy in Gαq overexpressing mice and in transgenic mice expressing high levels of wild-type Gαq. The consequence of cardiomyocyte apoptosis was a transition from compensated hypertrophy to a rapidly progressive and lethal cardiomyopathy. Progression from hypertrophy to apoptosis in vitro and in vivo was coincident with activation of p38 and Jun kinases. These data suggest a mechanism in which moderate levels of Gq signaling stimulate cardiac hypertrophy whereas high level Gq 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 hypertrophy to decompensated heart failure.

Original languageEnglish
Pages (from-to)10140-10145
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number17
DOIs
StatePublished - Aug 18 1998

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