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.
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Low NO levels (pM/nM) are physiological and related to activation of high-affinity primary binding targets such as soluble guanylyl cyclase and cytochrome c oxidase.
“It has been shown that low levels (pM/nM) are physiological and related to the activation of high affinity primary binding targets such as soluble guanylyl cyclase (sGC) and cytochrome c oxidase”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [863]
The nitrite level in cardiac tissue is a couple of times higher than in plasma due to an unknown form of active transport from blood to tissues or due to oxidation of endogenously generated NO to nitrite by ceruloplasmin, and serves as a significant extravascular pool for NO during tissue hypoxia.
“The nitrite level in cardiac tissue is a couple of times higher than that in plasma due to an unknown form of active transport from blood to tissues or due to the oxidation of endogenously generated-NO to nitrite by ceruloplasmin [96], and serves as a significant extravascular pool for NO during tissue hypoxia [97].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [96]
Mice deficient for ceruloplasmin show lower basal concentrations of plasma nitrite and less plasma nitrite elevation upon NO administration.
“This concept is confirmed in mice deficient for ceruloplasmin that showed lower basal concentrations of plasma nitrite and less plasma nitrite elevation upon NO administration [78].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [78]
The addition of NO to blood generates significant concentrations of plasma nitrite that involves copper oxidation, which was found to be ceruloplasmin dependent NO oxidation.
“It was also shown that the addition of NO to blood generates significant concentrations of plasma nitrite that involved copper oxidation, which was found to be ceruloplasmin dependent NO oxidation [78, 79].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [78]
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- Authors
- Shiva, S., Wang, X., Ringwood, L. A., Xu, X., Yuditskaya, S., Annavajjhala, V., Miyajima, H., Hogg, N., Harris, Z. L., & Gladwin, M. T.
- Affiliations
- National Institutes of Health (US)
- Johns Hopkins University (US)
- Hamamatsu University (JP)
- Medical College of Wisconsin (US)
- Corresponding author
- Gladwin, Mark T
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2006-08-13
- Volume
- 2
- Issue
- 9
- Pages
- 486-493
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W1973480138
- Cited by
- 359
- References
- 52
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 6 · 2023: 17 · 2022: 22 · 2021: 22 · 2020: 17 · 2019: 13 · 2018: 13 · 2017: 15 · 2016: 19 · 2015: 22 · 2014: 24 · 2013: 28 · 2012: 24
- FWCI
- 13.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- ceruloplasmin, nitric oxide homeostasis, multicopper oxidase, aceruloplasminemia, ischemia-reperfusion injury, liver infarction, hypoxia signaling, cytoprotection, nitrate
- MeSH terms
- Animals, Catalysis, Ceruloplasmin, Endocrine System, Erythrocytes, Female, Homeostasis, Humans, Liver, Male, Mice, Transgenic, Nitric Oxide, Nitrites, Oxidation-Reduction, Plasma, Vasodilation, Reperfusion Injury, Nitric Oxide Synthase, Mice, In Vitro Techniques
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