title: Nitric oxide-dependent induction of glutathione synthesis through increased expression of gamma-glutamylcysteine synthetase.
abstract: The nitric oxide (NO) donors S-nitrosopenicillamine or DetaNONOate, which release NO at a rate of 0-15 nM sec-1, were exposed to rat aortic vascular smooth muscle cells for a period of 0-24 h. This treatment resulted in an increase in total glutathione levels of two- to threefold under conditions where no cytotoxicity was detected. The signaling pathways do not involve activation of protein kinase G Ialpha nor are they cGMP dependent. Oxidation of reduced glutathione (GSH) was found after exposure to NO for 3-4 h at rates of formation at or above 8 nM sec-1. Increased intracellular GSH was due to enhanced expression of the rate-limiting enzyme for GSH synthesis, gamma-glutamylcysteine synthetase. Since NO has been shown previously to protect cells against oxidative stress, we propose that the increase in GSH by NO is a potential mechanism for enhancing the antioxidant defenses of the cell. This result also has important implications for identifying redox-sensitive cell signaling pathways that can be activated by NO.
authors.affiliation: Molecular and Cellular Division, Center for Free Radical Biology, University of Alabama at Birmingham, Volker Hall Room GO38, 1670 University Boulevard, Birmingham, Alabama, 35294-0019, USA.
authors.forename: D
authors.initials: D
authors.lastname: Moellering
authors.forename: J
authors.initials: J
authors.lastname: McAndrew
authors.forename: R P
authors.initials: RP
authors.lastname: Patel
authors.forename: T
authors.initials: T
authors.lastname: Cornwell
authors.forename: T
authors.initials: T
authors.lastname: Lincoln
authors.forename: X
authors.initials: X
authors.lastname: Cao
authors.forename: J L
authors.initials: JL
authors.lastname: Messina
authors.forename: H J
authors.initials: HJ
authors.lastname: Forman
authors.forename: H
authors.initials: H
authors.lastname: Jo
authors.forename: V M
authors.initials: VM
authors.lastname: Darley-Usmar
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal; D001013:Aorta, Thoracic; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D009569:Nitric Oxide; D005978:Glutathione; D006152:Cyclic GMP