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 H Schulman, Jonathan S. Stamler, Joshua Hare

Research output: Contribution to journalArticle

68 Citations (Scopus)

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
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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glutathione-independent formaldehyde dehydrogenase
Blood Vessels
Adrenergic Agents
Mouse Adh5 protein
Nitric Oxide
Adrenergic Agonists
Ryanodine Receptor Calcium Release Channel
Protein S
Nitric Oxide Synthase
Proteins
Hemodynamics
Calcium

Keywords

  • Excitation-contraction coupling
  • Nitroso-redox imbalance

ASJC Scopus subject areas

  • General

Cite this

Dynamic denitrosylation via S-nitrosoglutathione reductase regulates cardiovascular function. / Beigi, Farideh; Gonzalez, Daniel R.; Minhas, Khalid M.; Sun, Qi An; Foster, Matthew W.; Khan, Shakil A.; Treuer, Adriana V.; Dulce, Raul A.; Harrison, Robert W.; Saraiva, Roberto M.; Premer, Courtney; Schulman, Ivonne H; Stamler, Jonathan S.; Hare, Joshua.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 11, 13.03.2012, p. 4314-4319.

Research output: Contribution to journalArticle

Beigi, F, Gonzalez, DR, Minhas, KM, Sun, QA, Foster, MW, Khan, SA, Treuer, AV, Dulce, RA, Harrison, RW, Saraiva, RM, Premer, C, Schulman, IH, Stamler, JS & Hare, J 2012, 'Dynamic denitrosylation via S-nitrosoglutathione reductase regulates cardiovascular function', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 11, pp. 4314-4319. https://doi.org/10.1073/pnas.1113319109
Beigi, Farideh ; Gonzalez, Daniel R. ; Minhas, Khalid M. ; Sun, Qi An ; Foster, Matthew W. ; Khan, Shakil A. ; Treuer, Adriana V. ; Dulce, Raul A. ; Harrison, Robert W. ; Saraiva, Roberto M. ; Premer, Courtney ; Schulman, Ivonne H ; Stamler, Jonathan S. ; Hare, Joshua. / Dynamic denitrosylation via S-nitrosoglutathione reductase regulates cardiovascular function. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 11. pp. 4314-4319.
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