Dynamic denitrosylation via S -nitrosoglutathione reductase regulates cardiovascular function
- 24 February 2012
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (11), 4314-4319
- https://doi.org/10.1073/pnas.1113319109
Abstract
Although protein S-nitrosylation is increasingly recognized as mediating nitric oxide (NO) signaling, roles for protein denitrosylation in physiology remain unknown. Here, we show that S-nitrosoglutathione reductase (GSNOR), an enzyme that governs levels of S-nitrosylation by promoting protein denitrosylation, regulates both peripheral vascular tone and β-adrenergic agonist-stimulated cardiac contractility, previously ascribed exclusively to NO/cGMP. GSNOR-deficient mice exhibited reduced peripheral vascular tone and depressed β-adrenergic inotropic responses that were associated with impaired β-agonist-induced denitrosylation of cardiac ryanodine receptor 2 (RyR2), resulting in calcium leak. These results indicate that systemic hemodynamic responses (vascular tone and cardiac contractility), both under basal conditions and after adrenergic activation, are regulated through concerted actions of NO synthase/GSNOR and that aberrant denitrosylation impairs cardiovascular function. Our findings support the notion that dynamic S-nitrosylation/denitrosylation reactions are essential in cardiovascular regulation.Keywords
This publication has 50 references indexed in Scilit:
- Impaired S-Nitrosylation of the Ryanodine Receptor Caused by Xanthine Oxidase Activity Contributes to Calcium Leak in Heart FailureOnline Journal of Public Health Informatics, 2010
- Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophyProceedings of the National Academy of Sciences of the United States of America, 2010
- Endogenous S -nitrosothiols protect against myocardial injuryProceedings of the National Academy of Sciences of the United States of America, 2009
- Regulation of the Cardiac Muscle Ryanodine Receptor by O2 Tension and S-NitrosoglutathioneBiochemistry, 2008
- S-Nitrosylation of β-Arrestin Regulates β-Adrenergic Receptor TraffickingMolecular Cell, 2008
- RyR1 S-Nitrosylation Underlies Environmental Heat Stroke and Sudden Death in Y522S RyR1 Knockin MiceCell, 2008
- Tumour maintenance is mediated by eNOSNature, 2008
- Remodeling of ryanodine receptor complex causes “leaky” channels: A molecular mechanism for decreased exercise capacityProceedings of the National Academy of Sciences of the United States of America, 2008
- Deficient ryanodine receptor S -nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytesProceedings of the National Academy of Sciences of the United States of America, 2007
- The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholineNature, 1980