© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Increased basal contractility of cardiomyocytes overexpressing protein kinase C
and blunted positive inotropic response to endothelin-1
aDepartment of Cardiology and Angiology, University of Freiburg, D-79106 Freiburg, Germany
bGeorg-August-Universitaet Goettingen, Zentrum Innere Medizin, Department of Cardiology and Pneumology, Robert-Koch-Strasse 40, D-37075 Goettingen, Germany
cINSERM U533, F-44035 Nantes Cedex 01, France
* Corresponding author. Tel.: +49-551-396-380; fax: +49-551-392-953 stephane.baudet{at}intervet.com prestle{at}med.uni-goettingen.de
Objective: Protein kinase C (PKC) is thought to be involved in the regulation of the mammalian cardiac excitation–contraction coupling process by vasoactive peptides like endothelin-1 (ET-1). However, the demonstration of a causal link between activation of specific PKC isoforms and the increase in contractility mediated by ET-1 is still inferential. Methods: By means of adenovirus-mediated gene transfer, we specifically overexpressed PKC
in cultured adult rabbit ventricular myocytes (Ad-PKC). Myocyte shortening and [Ca2+]i transients under basal and ET-1-stimulated conditions were measured in Ad-PKC and Ad-LacZ control transfected cells. Results: Infection with Ad-PKC resulted in a strong, virus dose-dependent increase in PKC protein levels, whereas protein expression of other PKC isoforms remained unchanged. Using a multiplicity of infection of 100 plaque-forming units/myocyte, basal and cofactor-dependent PKC kinase activity was increased 28- and 90-fold, respectively, when compared to control. Myocyte basal fractional shortening and [Ca2+]i transient amplitude were both increased by 21% (P<0.05 each) in Ad-PKC transfected myocytes when compared to Ad-LacZ transfected control myocytes. The positive inotropic effect of ET-1 in control myocytes was markedly blunted in PKC-overexpressing myocytes. Conclusion: Specific overexpression of PKC in rabbit ventricular myocytes increases basal myocyte contractility and [Ca2+]i transients, and modifies their responsiveness to ET-1.
KEYWORDS Contractile function; e–c Coupling; Endothelins; Gene therapy; Myocytes; Protein kinases; Signal transduction
1 Present address: Stéphane Baudet, Intervet Pharma R&D, Internal Medicine II, BP 67131, F-49071 Beaucouzé Cedex, France.
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