title: Exogenous hydrogen sulfide inhibits superoxide formation, NOX-1 expression and Rac1 activity in human vascular smooth muscle cells.
abstract: The activity of NADPH oxidase (NOX) is blocked by nitric oxide (NO). Hydrogen sulfide (H(2)S) is also produced by blood vessels. It is reasonable to suggest that H(2)S may have similar actions to NO on NOX. In order to test this hypothesis, the effect of sodium hydrosulfide (NaHS) on O(2)(-) formation, the expression of NOX-1 (a catalytic subunit of NOX) and Rac(1) activity (essential for full NOX activity) in isolated vascular smooth muscle cells (hVSMCs) was investigated. hVSMCs were incubated with the thromboxane A(2) analogue U46619 +/- NaHS for 1 or 16 h, and O(2)(-) formation, NOX-1 expression and Rac(1) activity were assessed. The possible interaction between H(2)S and NO was also studied by using an NO synthase inhibitor, L-NAME, and an NO donor, DETA-NONOate. The role of K(ATP) channels was studied by using glibenclamide. NaHS inhibited O(2)(-) formation following incubation of 1 h (IC(50), 30 nM) and 16 h (IC(50), 20 nM), blocked NOX-1 expression and inhibited Rac(1) activity. These inhibitory effects of NaHS were mediated by the cAMP-protein-kinase-A axis. Exogenous H(2)S prevents NOX-driven intravascular oxidative stress through an a priori inhibition of Rac(1) and downregulation of NOX-1 protein expression, an effect mediated by activation of the adenylylcyclase-cAMP-protein-kinase-G system by H(2)S.
authors.affiliation: Bristol Heart Institute, University of Bristol, Bristol, UK. S.Muzaffar@bris.ac.uk
authors.forename: Saima
authors.initials: S
authors.lastname: Muzaffar
authors.forename: Nilima
authors.initials: N
authors.lastname: Shukla
authors.forename: Mark
authors.initials: M
authors.lastname: Bond
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Newby
authors.forename: Gianni D
authors.initials: GD
authors.lastname: Angelini
authors.forename: Anna
authors.initials: A
authors.lastname: Sparatore
authors.forename: Piero
authors.initials: P
authors.lastname: Del Soldato
authors.forename: Jamie Y
authors.initials: JY
authors.lastname: Jeremy
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009603:Nitroso Compounds / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013440:Sulfides / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D054086:KATP Channels; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D026902:Potassium Channel Blockers; C107953:RAC1 protein, human; D013440:Sulfides; D013481:Superoxides; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D020830:rac1 GTP-Binding Protein; D000262:Adenylyl Cyclases; C025451:sodium bisulfide; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester; D006862:Hydrogen Sulfide