Dynamic denitrosylation via S-nitrosoglutathione reductase regulates cardiovascular function

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

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70 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4314-4319
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number11
DOIs
StatePublished - Mar 13 2012

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Keywords

  • Excitation-contraction coupling
  • Nitroso-redox imbalance

ASJC Scopus subject areas

  • General

Cite this

Beigi, F., Gonzalez, D. R., Minhas, K. M., Sun, Q. A., Foster, M. W., Khan, S. A., Treuer, A. V., Dulce, R. A., Harrison, R. W., Saraiva, R. M., Premer, C., Schulman, I. H., Stamler, J. S., & Hare, J. M. (2012). Dynamic denitrosylation via S-nitrosoglutathione reductase regulates cardiovascular function. Proceedings of the National Academy of Sciences of the United States of America, 109(11), 4314-4319. https://doi.org/10.1073/pnas.1113319109