Protein kinase Calpha negatively regulates systolic and diastolic function in pathological hypertrophy.

Abstract

The protein kinase C (PKC) family is implicated in cardiac hypertrophy, contractile failure, and beta-adrenergic receptor (betaAR) dysfunction. Herein, we describe the effects of gain- and loss-of-PKCalpha function using transgenic expression of conventional PKC isoform translocation modifiers. In contrast to previously studied PKC isoforms, activation of PKCalpha failed to induce cardiac hypertrophy, but instead caused betaAR insensitivity and ventricular dysfunction. PKCalpha inhibition had opposite effects. Because PKCalpha is upregulated in human and experimental cardiac hypertrophy and failure, its effects were also assessed in the context of the Galphaq overexpression model (in which PKCalpha is transcriptionally upregulated). Normalization (inhibition) of PKCalpha activity in Galpha(q) hearts improved systolic and diastolic function, whereas further activation of PKCalpha caused a lethal restrictive cardiomyopathy with marked interstitial fibrosis. These results define pathological roles for PKCalpha as a negative regulator of ventricular systolic and diastolic function.

• Authors: Harvey S Hahn, Yehia Marreez, Amy Odley, Amber Sterbling, Martin G Yussman, K Chad Hilty, Ilona Bodi, Stephen B Liggett, Arnold Schwartz, Gerald W Dorn 2nd
• Journal: Circulation research (Circ Res) Vol. 93 Issue 11 Pg. 1111-9 (Nov 28 2003) ISSN: 1524-4571 [Electronic] United States
• PMID: 14605019 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adrenergic beta-Agonists
• Enzyme Inhibitors
• Peptides
• Receptors, Adrenergic, beta
• Prkca protein, mouse
• Protein Kinase C
• Protein Kinase C-alpha
• GTP-Binding Protein alpha Subunits, Gq-G11

Topics

• Adrenergic beta-Agonists (pharmacology)
• Animals
• Cardiomegaly (enzymology, genetics, physiopathology)
• Cardiomyopathies (enzymology, pathology)
• Cell Separation
• Diastole
• Disease Models, Animal
• Enzyme Activation (drug effects, genetics)
• Enzyme Inhibitors (pharmacology)
• GTP-Binding Protein alpha Subunits, Gq-G11 (genetics, metabolism)
• Mice
• Mice, Transgenic
• Myocytes, Cardiac (drug effects, enzymology, physiology)
• Patch-Clamp Techniques
• Peptides (genetics, metabolism, pharmacology)
• Protein Kinase C (antagonists & inhibitors, genetics, metabolism)
• Protein Kinase C-alpha
• Protein Transport (genetics)
• Receptors, Adrenergic, beta (metabolism)
• Signal Transduction (physiology)
• Systole
• Ventricular Dysfunction (drug therapy, enzymology, genetics)