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

Authors
Hahn-HS; Marreez-Y; Odley-A; Sterbling-A; Yussman-MG; Hilty-KC; Bodi-I; Liggett-SB; Schwartz-A; Dorn-GW 2nd
Source
Circ Res 2003 Nov; 93(11):1111-1119
NIOSHTIC No.
20029175
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.
Keywords
Heart; Heart-rate; Fibrosis; Pharmacology; Enzymology; Diseases; Models; Enzymes; Enzyme-inhibitors; Laboratory-animals; Animals; Animal-studies; Peptides; Genetics
Contact
G.W. Dorn II, Department of Internal Medicine, University of Cincinnati Medical Center, 231 Albert B. Sabin Way, Cincinnati, Ohio 45267-0542, USA
CODEN
CIRUAL
Publication Date
20031128
Document Type
Journal Article
Email Address
dorngw@ucmail.uc.edu
Funding Type
Grant
Fiscal Year
2004
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-022619
Issue of Publication
11
ISSN
0009-7330
Source Name
Circulation Research
State
OH
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