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Dynamic denitrosylation via S-nitrosoglutathione reductase regulates cardiovascular function.


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 ?-adrenergic agonist-stimulated cardiac contractility, previously ascribed exclusively to NO/cGMP. GSNOR-deficient mice exhibited reduced peripheral vascular tone and depressed ?-adrenergic inotropic responses that were associated with impaired ?-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.

SUBMITTER: Beigi F 

PROVIDER: S-EPMC3306718 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Dynamic denitrosylation via S-nitrosoglutathione reductase regulates cardiovascular function.

Beigi Farideh F   Gonzalez Daniel R DR   Minhas Khalid M KM   Sun Qi-An QA   Foster Matthew W MW   Khan Shakil A SA   Treuer Adriana V AV   Dulce Raul A RA   Harrison Robert W RW   Saraiva Roberto M RM   Premer Courtney C   Schulman Ivonne Hernandez IH   Stamler Jonathan S JS   Hare Joshua M JM  

Proceedings of the National Academy of Sciences of the United States of America 20120224 11


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 periph  ...[more]

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