Journal
CIRCULATION RESEARCH
Volume 93, Issue 11, Pages 1111-1119Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000105087.79373.17
Keywords
systolic and diastolic heart failure; protein kinase C; interstitial fibrosis; restrictive cardiomyopathy
Funding
- NHLBI NIH HHS [HL52310, P0HL22619, HL07382] Funding Source: Medline
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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 Galphaq 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.
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