title: 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 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.
authors.affiliation: Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Farideh
authors.initials: F
authors.lastname: Beigi
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Gonzalez
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Minhas
authors.forename: Qi-An
authors.initials: QA
authors.lastname: Sun
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Foster
authors.forename: Shakil A
authors.initials: SA
authors.lastname: Khan
authors.forename: Adriana V
authors.initials: AV
authors.lastname: Treuer
authors.forename: Raul A
authors.initials: RA
authors.lastname: Dulce
authors.forename: Robert W
authors.initials: RW
authors.lastname: Harrison
authors.forename: Roberto M
authors.initials: RM
authors.lastname: Saraiva
authors.forename: Courtney
authors.initials: C
authors.lastname: Premer
authors.forename: Ivonne Hernandez
authors.initials: IH
authors.lastname: Schulman
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Stamler
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000426:Alcohol Dehydrogenase; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects; D003971:Diastole / Q000187:drug effects; D005260:Female; D005980:Glutathione Reductase / Q000172:deficiency / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D015538:Nitrosation; D021381:Protein Transport / Q000187:drug effects; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; C483598:Adh5 protein, mouse; D000426:Alcohol Dehydrogenase; D019001:Nitric Oxide Synthase; D005980:Glutathione Reductase; D007545:Isoproterenol; D002118:Calcium