The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.
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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“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
Citations
Cites
Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation
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Self-citationC ERULOPLASMIN M ETABOLISM AND F UNCTION
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Enzyme-independent formation of nitric oxide in biological tissues
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The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum.
Osaki, S., Johnson, D. A., & Frieden, E. (1966) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)96527-0 · Cited by 679
Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver
Duranski, M. R., Greer, J. J. M., Dejam, A., Jaganmohan, S., Hogg, N., Langston, W., Patel, R. P., Yet, S.-F., Wang, X., Kevil, C. G., et al. (2005) · Journal of Clinical Investigation · doi:10.1172/jci22493 · Cited by 674 · cited 1×
“In tissues, near-physiological concentrations of nitrite (”
Self-citationThe emerging biology of the nitrite anion
Gladwin, M. T., Schechter, A. N., Kim-Shapiro, D. B., Patel, R. P., Hogg, N., Shiva, S., Cannon, R. O., Kelm, M., Wink, D. A., Espey, M. G., et al. (2005) · Nature Chemical Biology · doi:10.1038/nchembio1105-308 · Cited by 609
Self-citationWebb, A., Bond, R., McLean, P., Uppal, R., Benjamin, N., & Ahluwalia, A. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402927101 · Cited by 608 · cited 1×
“In tissues, near-physiological concentrations of nitrite (”
Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals
Kleinbongard, P., Dejam, A., Lauer, T., Rassaf, T., Schindler, A., Picker, O., Scheeren, T., Gödecke, A., Schrader, J., Schulz, R., et al. (2003) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(03)00406-4 · Cited by 586
Aceruloplasminemia: molecular characterization of this disorder of iron metabolism.
Harris, Z. L., Takahashi, Y., Miyajima, H., Serizawa, M., MacGillivray, R. T., & Gitlin, J. D. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.7.2539 · Cited by 558 · cited 1×
“Ceruloplasmin has ferroxidase activity that is responsible for the oxidation of ferrous iron to its ferric form, which is necessary for efficient iron efflux from the cel”
BackgroundSelf-citationEnzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control
Huang, Z. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24650 · Cited by 520
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Metadata
- 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 (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › 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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