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Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis

Nature Chemical Biology volume 2, pages 486–493 (2006)Cite this article

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.

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Figure 1: Plasma has NO oxidase activity.
Figure 2: Redox-sensitive proteins of high molecular weight are responsible for plasma NO oxidase activity.
Figure 3: Ceruloplasmin as an NO oxidase.
Figure 4: Ceruloplasmin is a plasma NO oxidase.
Figure 5: Ceruloplasmin deficiency results in decreased plasma nitrite.
Figure 6: Ceruloplasmin knockout mice sustain more I/R-induced injury than wild-type mice, and nitrite is cytoprotective.

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Acknowledgements

We would like to thank D. Lefer and M. Duranski for generous instruction in the performance of the hepatic I/R protocol. We thank P. Fox for helpful discussions about ceruloplasmin.

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Authors and Affiliations

  1. Vascular Medicine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Sruti Shiva, Xunde Wang, Lorna A Ringwood, Susan Yuditskaya, Vidhya Annavajjhala & Mark T Gladwin

  2. Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Sruti Shiva, Xunde Wang, Lorna A Ringwood, Susan Yuditskaya & Mark T Gladwin

  3. Department of Anesthesia and Critical Care Medicine, Johns Hopkins Hospital and School of Medicine, Baltimore, 21287, Maryland, USA

    Xueying Xu & Zena Leah Harris

  4. First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan

    Hiroaki Miyajima

  5. Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, 53226, Wisconsin, USA

    Neil Hogg

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Contributions

S.S., acquisition, analysis and interpretation of data, and drafting and revision of the manuscript; X.W., L.A.R., X.X., S.Y. and V.A., acquisition of data; H.M., supplying of critical samples; N.H., acquisition, analysis and interpretation of data; Z.L.H. and M.T.G., analysis and interpretation of data, and drafting and critical review of the manuscript.

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Correspondence to Mark T Gladwin.

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Shiva, S., Wang, X., Ringwood, L. et al. Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis. Nat Chem Biol 2, 486–493 (2006). https://doi.org/10.1038/nchembio813

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