Cardiovascular Research Advance Access originally published online on September 19, 2007
Cardiovascular Research 2008 77(2):353-361; doi:10.1093/cvr/cvm018
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Targeting of phospholamban by peroxynitrite decreases β-adrenergic stimulation in cardiomyocytes
1 Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University, 304 Hamilton Hall, 1645 Neil Avenue, 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. Tel: +1 614 688 7905; fax: +1 614 688 7999. E-mail address: ziolo.1{at}osu.edu
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 Ca2+ transients were simultaneously recorded. PLB phosphorylation was measured via western blot. Myocytes were superfused with isoproterenol, a β-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 β-adrenergic-stimulated PLB–/– myocytes. Western blot analyses 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 β-adrenergic stimulation by reducing PLBSer16 phosphorylation via protein phosphatase activation. This peroxynitrite-induced decrease in PLB phosphorylation may be a key mechanism in the β-adrenergic dysfunction observed in many cardiomyopathies.
KEYWORDS E-C coupling; SR Function; Calcium (cellular); Protein Phosphorylation; Protein Phosphatases
Time for primary review: 27 days
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