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.

Nitrite confers protection against myocardial infarction: Role of xanthine oxidoreductase, NADPH oxidase and KATP channels

“…Approximately 80-90% of plasma nitrite is derived from endothelial nitric oxidase synthase derived nitric oxide [2]. Recently it has been shown that plasma cerulloplasmin has a nitric oxide oxidase activity, and may play a role in the conversion of nitric oxide to nitrite in vivo [3]. The nitrite anion, which is present between 0.2 and 10 μM in the blood and tissues [4,5], may represent a storage form of nitric oxide that is made available under conditions of oxygen deprivation to maintain cell survival.…”

Enjoy your heart-beets. The role of dietary inorganic nitrate in cardiovascular health

“…However, a small fraction of the NO is converted to a biologically active NO 2 -either by ceruloplasmin [18] or via NO autoxidation (Fig. 2).…”

Pharmacology and therapeutic role of inorganic nitrite and nitrate in vasodilatation

“…NO produced through this pathway has been proposed to represent a NOSindependent alternative to the classical pathway in which NO is produced by oxidation of L-arginine in a reaction catalyzed by NOS . Under normal physiological pH and oxygen tension, nitrite is an endogenous substance produced via the oxidation of NO (in cells by cytochrome C oxidase (Torres et al, 2000), in blood principally by ceruloplasmin; Shiva et al, 2006), and for many years nitrite was simply considered a relatively inert metabolic end-product of NO. However in the past decade, it has become apparent that under certain conditions nitrite exerts potent biological effects, and several research groups have identified that -particularly at low pH and oxygen tension -nitrite is reduced by various nitrite reductases to NO (Cosby et al, 2003;Webb et al, 2004;Rassaf et al, 2007;Shiva et al, 2007a;Feelisch et al, 2008;Webb et al, 2008a;Aamand et al, 2009;Totzeck et al, 2012a).…”