Dual actions of the Galpha(q) agonist Pasteurella multocida toxin to promote cardiomyocyte hypertrophy and enhance apoptosis susceptibility.

Abstract

Previous attempts to delineate the consequences of Galpha (q) activation in cardiomyocytes relied largely on molecular strategies in cultures or transgenic mice. Modest levels of wild-type Galpha(q) overexpression induce stable cardiac hypertrophy, whereas intense Galpha(q) stimulation induces cardiomyocyte apoptosis. The precise mechanism(s) whereby traditional targets of Galpha (q) subunits that induce hypertrophy also trigger cardiomyocyte apoptosis is not obvious and is explored with recombinant Pasteurella multocida toxin (rPMT, a Galpha(q) 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 Galpha(q)-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.

• Authors: Abdelkarim Sabri, Brenda A Wilson, Susan F Steinberg
• Journal: Circulation research (Circ Res) Vol. 90 Issue 8 Pg. 850-7 (May 03 2002) ISSN: 1524-4571 [Electronic] United States
• PMID: 11988485 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Bacterial Proteins
• Bacterial Toxins
• Pasteurella multocida toxin
• Proto-Oncogene Proteins
• Recombinant Proteins
• Hydrogen Peroxide
• ErbB Receptors
• Akt1 protein, rat
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Protein Kinase C
• Mitogen-Activated Protein Kinases
• Type C Phospholipases
• GTP-Binding Protein alpha Subunits, Gq-G11
• Heterotrimeric GTP-Binding Proteins

Topics

• Animals
• Animals, Newborn
• Apoptosis
• Bacterial Proteins
• Bacterial Toxins (pharmacology)
• Cardiomegaly (chemically induced, pathology)
• Cells, Cultured
• Drug Synergism
• ErbB Receptors (metabolism)
• GTP-Binding Protein alpha Subunits, Gq-G11
• Heterotrimeric GTP-Binding Proteins (agonists)
• Hydrogen Peroxide (pharmacology)
• Mitogen-Activated Protein Kinases (metabolism)
• Models, Biological
• Myocardium (cytology, enzymology, metabolism)
• Protein Kinase C (metabolism)
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Rats
• Recombinant Proteins (pharmacology)
• Signal Transduction
• Type C Phospholipases (metabolism)