Published online before print March 21, 2002, doi: 10.1161/01.RES.0000016165.23795.1F
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Submitted on November 14, 2001
Revised on March 12, 2002
Accepted on March 12, 2002
Dual Actions of the G
q Agonist Pasteurella multocida Toxin to Promote Cardiomyocyte Hypertrophy and Enhance Apoptosis Susceptibility
Abdelkarim Sabri ;
From the Departments of Pharmacology and Medicine (A.S., S.F.S.), College of Physicians and Surgeons, Columbia University, New York, NY; and the Department of Microbiology (B.A.W.), University of Illinois at Urbana-Champaign, Urbana, Ill.
* To whom correspondence should be addressed. E-mail: sfs1{at}columbia.edu.
Previous attempts to delineate the consequences of Gq activation in cardiomyocytes relied largely on molecular strategies in cultures or transgenic mice. Modest levels of wild-type Gq overexpression induce stable cardiac hypertrophy, whereas intense Gq stimulation induces cardiomyocyte apoptosis. The precise mechanism(s) whereby traditional targets of Gq subunits that induce hypertrophy also trigger cardiomyocyte apoptosis is not obvious and is explored with recombinant Pasteurella multocida toxin (rPMT, a Gq agonist). Cells chronically 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 Gq-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.
Key words: Gq • protein kinase C • Akt • hypertrophy • apoptosis
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