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Cardiovascular Research 2004 63(3):561-572; doi:10.1016/j.cardiores.2004.01.026
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Effects of {alpha}1-adrenergic stimulation on normal and hypertrophied mouse hearts. Relation to caveolin-3 expression

Natalia N Petrashevskaya, Ilona Bodi, Sheryl E Koch, Shahab A Akhter and Arnold Schwartz*

Department of Surgery, Cardiovascular Research Center, Institute of Molecular Pharmacology and Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati OH 45267-0828, USA

* Corresponding author. Tel.: +1-513-558-2400; fax: +1-513-558-1778. Email address: schwara{at}email.uc.edu

Background: Modulation of the transduction efficiency through G-protein coupled receptors, caused by external stimulation, is essential in designing antihypertrophic treatment strategies in the dysfunctional heart. We compared protein-kinase C (PKC)-dependent regulation of positive inotropic effect via {alpha}1-adrenoreceptor (ADR)/Gq protein in hyperdynamic versus hypertrophied myocardium. Methods: Inotropic (work performing isolated heart) and cellular effects of {alpha}1-adrenoreceptor stimulation were studied in nontransgenic (Ntg) and transgenic (Tg) mice with cardiac specific overexpression of L-type voltage-dependent calcium channels (L-type VDCC). Results: Transgenic hyperdynamic and hypertrophic myocardium (due to overexpression of the L-type VDCC {alpha}1 subunit) were characterized by a lack of positive inotropic effect (PIE) to {alpha}1-ADR stimulation with phenylephrine (PE), as compared to a positive response in Ntg hearts. This was partially restored by PKC inhibition with chelerythrine and staurosporine only at the hyperdynamic stage. The inability of PKC inhibition to increase positive inotropy was associated with markedly decreased cardiac-specific caveolin-3 expression, and no changes in G{alpha}q, PLC-β1, caveolin-1 and {alpha}1-adrenoreceptor expression. Conclusion: In the hyperdynamic myocardium, PKC activation may be one of the switches responsible for an impaired {alpha}1-adrenergic positive inotropic response. In the hypertrophied myocardium, the interruption of the transduction from G{alpha}q-protein coupled receptors to downstream effectors may be due to the down-regulation of caveolin-3 expression.

KEYWORDS Myocardium; Receptors; Adrenergic; Alpha; Calcium; Hypertrophy; Signal transduction

Time for primary review 27 days


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