Work

Targeting of phospholamban by peroxynitrite decreases β-adrenergic stimulation in cardiomyocytes

Year: 2007

Type: article

Abstract: AIMS: Peroxynitrite production increases during the pathogenesis of numerous cardiac disorders (e.g. heart failure). However, limited studies have investigated the mechanism through which peroxynitrite exerts anti-adrenergic effects. Thus, the purpose of this study is to investigate the contribution of phospholamban (PLB), a critical excitation-contraction coupling protein, to the peroxynitrite-induced dysfunction. METHODS AND RESULTS: Isolated myocytes from wild-type (WT, CF-1) and PLB knockout (PLB(-/-)) mice were stimulated at 1 Hz, and myocyte shortening and Ca(2+) transients were simultaneously recorded. PLB phosphorylation was measured via western blot. Myocytes were superfused with isoproterenol, a beta-adrenergic agonist, and SIN-1, a peroxynitrite donor. SIN-1 superfusion dramatically decreased isoproterenol-stimulated Ca(2+) transients and myocyte shortening in WT myocytes. These effects were inhibited upon addition of the peroxynitrite decomposition catalyst, FeTPPS. Surprisingly, SIN-1 had no functional effect on beta-adrenergic-stimulated PLB(-/-) myocytes. Western blot analyses revealed that SIN-1 significantly decreased isoproterenol-stimulated PLB(Ser16) phosphorylation. Experiments with the protein phosphatase inhibitor, okadaic acid, alleviated the SIN-1-induced functional effects and the decrease in PLB phosphorylation. CONCLUSIONS: The peroxynitrite donor SIN-1 decreases beta-adrenergic stimulation by reducing PLB(Ser16) phosphorylation via protein phosphatase activation. This peroxynitrite-induced decrease in PLB phosphorylation may be a key mechanism in the beta-adrenergic dysfunction observed in many cardiomyopathies.

Source: Cardiovascular Research

DOI: 10.1093/cvr/cvm018

Authors: Mark J. Kohr, Honglan Wang, Debra G. Wheeler, Murugesan Velayutham, Jay L. Zweier, Mark T. Ziolo

Institution: The Ohio State University

Language: English

Topic: Cardiac electrophysiology and arrhythmias

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: bronze

Funders: American Heart Association, University of Cincinnati, National Institutes of Health, National Heart, Lung, and Blood Institute