title: Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis.
abstract: Nitrite represents a bioactive reservoir of nitric oxide (NO) that may modulate vasodilation, respiration and cytoprotection after ischemia-reperfusion injury. Although nitrite formation is thought to occur via reaction of NO with oxygen, this third-order reaction cannot compete kinetically with the reaction of NO with hemoglobin to form nitrate. Indeed, the formation of nitrite from NO in the blood is limited when plasma is substituted with physiological buffers, which suggests that plasma contains metal-based enzymatic pathways for nitrite synthesis. We therefore hypothesized that the multicopper oxidase, ceruloplasmin, could oxidize NO to NO+, with subsequent hydration to nitrite. Accordingly, plasma NO oxidase activity was decreased after ceruloplasmin immunodepletion, in ceruloplasmin knockout mice and in people with congenital aceruloplasminemia. Compared to controls, plasma nitrite concentrations were substantially reduced in ceruloplasmin knockout mice, which were more susceptible to liver infarction after ischemia and reperfusion. The extent of hepatocellular infarction normalized after nitrite repletion. These data suggest new functions for the multicopper oxidases in endocrine NO homeostasis and nitrite synthesis, and they support the hypothesis that physiological concentrations of nitrite contribute to hypoxic signaling and cytoprotection.
authors.affiliation: Vascular Medicine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.forename: Xunde
authors.initials: X
authors.lastname: Wang
authors.forename: Lorna A
authors.initials: LA
authors.lastname: Ringwood
authors.forename: Xueying
authors.initials: X
authors.lastname: Xu
authors.forename: Susan
authors.initials: S
authors.lastname: Yuditskaya
authors.forename: Vidhya
authors.initials: V
authors.lastname: Annavajjhala
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miyajima
authors.forename: Neil
authors.initials: N
authors.lastname: Hogg
authors.forename: Zena Leah
authors.initials: ZL
authors.lastname: Harris
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
mesh_terms: D000818:Animals; D002384:Catalysis; D002570:Ceruloplasmin / Q000235:genetics / Q000378:metabolism*; D004703:Endocrine System / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000098:blood supply; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000097:blood* / Q000378:metabolism; D009573:Nitrites / Q000097:blood* / Q000627:therapeutic use; D010084:Oxidation-Reduction; D010949:Plasma / Q000201:enzymology; D015427:Reperfusion Injury / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D009573:Nitrites; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D002570:Ceruloplasmin