Effects of α1-adrenergic stimulation on normal and hypertrophied mouse hearts. Relation to caveolin-3 expression

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Abstract

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 α1-adrenoreceptor (ADR)/Gq protein in hyperdynamic versus hypertrophied myocardium. Methods: Inotropic (work performing isolated heart) and cellular effects of α1-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 α1 subunit) were characterized by a lack of positive inotropic effect (PIE) to α1-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 Gαq, PLC-β1, caveolin-1 and α1-adrenoreceptor expression. Conclusion: In the hyperdynamic myocardium, PKC activation may be one of the switches responsible for an impaired α1-adrenergic positive inotropic response. In the hypertrophied myocardium, the interruption of the transduction from Gαq-protein coupled receptors to downstream effectors may be due to the down-regulation of caveolin-3 expression. © 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

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Petrashevskaya, N. N., Bodi, I., Koch, S. E., Akhter, S. A., & Schwartz, A. (2004). Effects of α1-adrenergic stimulation on normal and hypertrophied mouse hearts. Relation to caveolin-3 expression. Cardiovascular Research, 63(3), 561–572. https://doi.org/10.1016/j.cardiores.2004.01.026

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