title: Reactive oxygen and nitrogen species regulate inducible nitric oxide synthase function shifting the balance of nitric oxide and superoxide production.
abstract: Inducible NOS (iNOS) is induced in diseases associated with inflammation and oxidative stress, and questions remain regarding its regulation. We demonstrate that reactive oxygen/nitrogen species (ROS/RNS) dose-dependently regulate iNOS function. Tetrahydrobiopterin (BH4)-replete iNOS was exposed to increasing concentrations of ROS/RNS and activity was measured with and without subsequent BH4 addition. Peroxynitrite (ONOO(-)) produced the greatest change in NO generation rate, approximately 95% decrease, and BH4 only partially restored this loss of activity. Superoxide (O2(.-)) greatly decreased NO generation, however, BH4 addition restored this activity. Hydroxyl radical ((.)OH) mildly decreases NO generation in a BH4-dependent manner. iNOS was resistant to H2O2 with only slightly decreased NO generation with up to millimolar concentrations. In contrast to the inhibition of NO generation, ROS enhanced O2(.-) production from iNOS, while ONOO(-) had the opposite effect. Thus, ROS promote reversible iNOS uncoupling, while ONOO(-) induces irreversible enzyme inactivation and decreases both NO and O2(.-) production.
authors.affiliation: The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210-1252, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Druhan
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051381:Rats; D026361:Reactive Nitrogen Species / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D016877:Oxidants; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D013481:Superoxides; D001708:Biopterins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C003402:sapropterin