Dual actions of the Gαq agonist Pasteurella multocida toxin to promote cardiomyocyte hypertrophy and enhance apoptosis susceptibility

Abdelkarim Sabri, Brenda A. Wilson, Susan F. Steinberg

Research output: Contribution to journalArticlepeer-review

Abstract

Previous attempts to delineate the consequences of Gαq activation in cardiomyocytes relied largely on molecular strategies in cultures or transgenic mice. Modest levels of wild-type Gαq overexpression induce stable cardiac hypertrophy, whereas intense Gαq stimulation induces cardiomyocyte apoptosis. The precise mechanism(s) whereby traditional targets of Gαq subunits that induce hypertrophy also trigger cardiomyocyte apoptosis is not obvious and is explored with recombinant Pasteurella multocida toxin (rPMT, a Gαq agonist). Cells cultured with rPMT display cardiomyocyte enlargement, sarcomeric organization, and increased atrial natriuretic factor expression in association with activation of phospholipase C, novel protein kinase C (PKC) isoforms, extracellular signal-regulated protein kinase (ERK), and (to a lesser extent) JNK/p38-MAPK. rPMT stimulates the ERK cascade via epidermal growth factor (EGF) receptor transactivation in cardiac fibroblasts, but EGF receptor transactivation plays no role in ERK activation in cardiomyocytes. Surprisingly, rPMT (or novel PKC isoform activation by PMA) decreases basal Akt phosphorylation; rPMT prevents Akt phosphorylation by EGF or IGF-1 and functionally augments cardiomyocyte apoptosis in response to H2O2. These results identify a Gαq-PKC pathway that represses basal Akt phosphorylation and impairs Akt stimulation by survival factors. Because inhibition of Akt enhances cardiomyocyte susceptibility to apoptosis, this pathway is predicted to contribute to the transition from hypertrophy to cardiac decompensation and could be targeted for therapy in heart failure.

Original languageEnglish (US)
Pages (from-to)850-857
Number of pages8
JournalCirculation Research
Volume90
Issue number8
DOIs
StatePublished - May 3 2002

Keywords

  • Akt
  • Apoptosis
  • G
  • Hypertrophy
  • Protein kinase C

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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