Dynamic Denitrosylation Via S-nitrosoglutathione Reductase Regulates Cardiovascular Function

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2012 Feb 28

PMID 22366318

Citations 77

Authors

Farideh Beigi

Daniel R Gonzalez

Khalid M Minhas

Qi-An Sun

Matthew W Foster

Shakil A Khan

Adriana V Treuer

Raul A Dulce

Robert W Harrison

Roberto M Saraiva

Courtney Premer

Ivonne Hernandez Schulman

Jonathan S Stamler

Joshua M Hare

Affiliations

Soon will be listed here.

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.

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