Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 19, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm018
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Targeting of Phospholamban by Peroxynitrite Decreases b-adrenergic Stimulation in Cardiomyocytes
1 Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA
2 Department of Internal Medicine: Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA
Corresponding Author: Mark T Ziolo Department of Physiology & Cell Biology, The Ohio State University, 304 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA, Telephone: 614-688-7905, Fax: 614-688-7999, Email: ziolo.1{at}osu.edu
OBJECTIVE: 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: Isolated myocytes from wildtype (WT, CF-1) and PLB knockout (PLB-/-) mice were field stimulated at 1 Hz and shortening and Ca2 + transients were simultaneously recorded. PLB phosphorylation was measured via Western blot.
RESULTS: Myocytes were superfused with isoproterenol, a b-adrenergic agonist, and SIN-1, a peroxynitrite donor. SIN-1 superfusion dramatically decreased isoproterenol-stimulated Ca2 + 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 b-adrenergic-stimulated PLB-/- myocytes. Western blot revealed that SIN-1 significantly decreased isoproterenol-stimulated PLBSer16 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 b-adrenergic stimulation by reducing PLBSer16 phosphorylation via protein phosphatase activation. This peroxynitrite-induced decrease in PLB phosphorylation may be a key mechanism in the b-adrenergic dysfunction observed in many cardiomyopathies.
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