Nitrite as Regulator of Hypoxic Signaling in Mammalian Physiology
Open accessAbstract
In this review we consider the effects of endogenous and pharmacological levels of nitrite under conditions of hypoxia. In humans, the nitrite anion has long been considered as metastable intermediate in the oxidation of nitric oxide radicals to the stable metabolite nitrate. This oxidation cascade was thought to be irreversible under physiological conditions. However, a growing body of experimental observations attests that the presence of endogenous nitrite regulates a number of signaling events along the physiological and pathophysiological oxygen gradient. Hypoxic signaling events include vasodilation, modulation of mitochondrial respiration, and cytoprotection following ischemic insult. These phenomena are attributed to the reduction of nitrite anions to nitric oxide if local oxygen levels in tissues decrease. Recent research identified a growing list of enzymatic and nonenzymatic pathways for this endogenous reduction of nitrite. Additional direct signaling events not involving free nitric oxide are proposed. We here discuss the mechanisms and properties of these various pathways and the role played by the local concentration of free oxygen in the affected tissue. © 2009 Wiley Periodicals, Inc. Med Res Rev, 29, No. 5, 683–741, 2009
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Nitrite is a circulating reservoir of NO, which can be reduced by haem proteins, xanthine oxidoreductase, and components of the mitochondrial electron transport chain; the reaction rate increases as oxygen tension declines.
“Nitrite is now considered a circulating reservoir of NO, which can be reduced by haem proteins, xanthine oxidoreductase, and components of the mitochondrial electron transport chain. The reaction rate increases as oxygen tension declines [36,37,38].”
From Dietary Nitrate-Rich Vegetables as Natural Modulators of Health: Mechanisms and Benefits in Ageing Populations (2026) · cites this paper as [36]
Section 8 calls plasma nitrite a major circulating NO storage pool. Section 7 identifies haem proteins, xanthine oxidase, and mitochondrial respiratory-chain components as nitrite reductases, and the Introduction describes additional pathways becoming active as oxygen falls. The unqualified claim about reaction rate is too broad: Section 7 reports that haemoglobin reduction peaks near its oxygen half-saturation point, while one xanthine-oxidase pathway is not strongly affected by oxygen. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHemoglobin, myoglobin, neuroglobin, xanthine oxidoreductase, aldehyde oxidase, carbonic anhydrase, eNOS, and mitochondrial enzymes have all been identified as having a role in nitrite bioactivation.
“Hemoglobin, myoglobin, neuroglobin, xanthine oxidoreductase, aldehyde oxidase, carbonic anhydrase, eNOS, and mitochondrial enzymes have all been identified with having a role in nitrite bioactivation (fig.1).14,15”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [14]
Section 7 identifies hemoglobin, myoglobin, xanthine oxidase, aldehyde oxidase, eNOS, and mitochondrial respiratory-chain components as participants in nitrite reduction to NO (page numbers unavailable). The passages retrieved from our copy do not identify neuroglobin or carbonic anhydrase as nitrite-bioactivation pathways, so the full list is not supported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredComponents of the respiratory chain can reduce nitrite to NO.
“Sruti Shiva (University of Pittsburgh) reviewed a number of studies demonstrating that components of the respiratory chain can reduce nitrite to NO (refs. 4,9)”
From Nitrate and nitrite in biology, nutrition and therapeutics (2009) · cites this paper as [4]
The body converts inorganic nitrate and nitrite, whether produced internally or consumed in the diet, into nitric oxide and other bioactive nitrogen oxides.
“Inorganic nitrate and nitrite from endogenous or dietary sources are metabolized in vivo to nitric oxide (NO) and other bioactive nitrogen oxides.”
From Nitrate and nitrite in biology, nutrition and therapeutics (2009) · cites this paper as [4]
Nitrate and nitrite are metabolized in blood and tissues to produce NO and other bioactive nitrogen oxides, providing an alternative to the classical L-arginine-NOS-NO signaling pathway.
“However, a new view is evolving with the accumulating evidence that nitrate and nitrite metabolism occurs in blood and tissues to form NO and other bioactive nitrogen oxides, representing an alternative to ‘classical’ L-arginine–NO synthase–NO signaling1–5.”
From Nitrate and nitrite in biology, nutrition and therapeutics (2009) · cites this paper as [4]
Under hypoxic conditions, when oxygen-dependent NO synthases may malfunction, nitrite reduction is greatly increased.
“In situations of hypoxia, when the oxygen-dependent NO synthases may become dysfunctional, nitrite reduction is instead greatly enhanced.”
From Nitrate and nitrite in biology, nutrition and therapeutics (2009) · cites this paper as [4]
The one-electron reduction of nitrite to NO can be catalyzed by many enzymatic and non-enzymatic pathways.
“It is now clear that the one-electron reduction of nitrite to NO can be catalyzed by numerous enzymatic as well as non-enzymatic pathways1,4.”
From Nitrate and nitrite in biology, nutrition and therapeutics (2009) · cites this paper as [4]
The nitrate-nitrite-nitric oxide pathway may serve as a backup system to ensure nitric oxide generation during ischemic/hypoxic conditions when oxygen-dependent NOSs may be malfunctioning.
“may serve as a backup system to ensure nitric oxide generation during ischemic/hypoxic conditions when the oxygen-dependent NOSs may be malfunctioning.14,15”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [14]
More recent observations indicate that the ADMA/l-arginine ratios in plasma may be a better marker than either metabolite assessed independently.
“More recent observations indicate that the ADMA/l-arginine ratios in plasma may be a better marker than either metabolite assessed independently (75, 589, 606, 790, 966).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [966]
Nitrite as a reservoir can be further reduced to NO via numerous pathways in blood and tissue, and this process is accelerated under hypoxic conditions.
“Nitrite as a reservoir can be further reduced to NO via numerous pathways in blood and tissue, and this process is indeed accelerated under hypoxic conditions.44 -47”
From Dietary nitrate supplementation improves revascularization in chronic ischemia (2012) · cites this paper as [47]
Nitrite can be reduced to NO in an oxygen-dependent manner by a variety of enzymatic and non-enzymatic pathways.
“Nitrite can be reduced to NO in an oxygen-dependent manner by a variety of enzymatic and non-enzymatic pathways [22].”
From On the chemical biology of the nitrite/sulfide interaction (2015) · cites this paper as [22]
Differential reactivity of nitrite reduction versus oxidation controlled by oxygen tension underlies the model in which nitrite selectively produces NO during graded hypoxia.
“This differential reactivity of nitrite reduction versus oxidation being controlled by oxygen tension (i.e. presence of deoxygenated vs oxygenated hemoglobin / myoglobin) illustrates the biochemical mechanism underlying the proposed model in which nitrite can selectively produce NO during graded hypoxia [5, 25-28].”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [5]
Generation of NO from nitrite reduction can occur under conditions that span a range of oxygen tensions and pH observed over the pathophysiological spectrum.
“The more recent interest in nitrite biology stems largely from the realization that the generation of NO from nitrite reduction can occur under conditions that span a range of oxygen tensions and pH observed over the pathophysiological spectrum [5-7].”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [5]
Most literature reports show that metallo-protein mediated nitrite reduction becomes more prominent with hypoxia.
“most literature reports show that metallo-protein mediated nitrite reduction becomes more prominent with hypoxia [5]”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [5]
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References 271 · Cited by 435
Research works printed but not linked: 5
- [61]Liu X Miller M Joshi M Thomas D Lancaster J Accelerated reaction of nitric oxide with O2 within the hydrophobic interior of biological membranes Proc Natl Acad Sci USA 1998 95 2175 2179 9482858 PMC19287
- [111]Huang Z Shiva S Kim-Shapiro D Patel R Ringwood L Irby C Huang K Ho C Hogg N Schechter A Gladwin M Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control J Clin Invest 2005 115 2099 2107 16041407 PMC1177999
- [134]Rassaf T Flögel U Drexhage C Hendgen-Cotta U Kelm M Schrader J Nitrite reductase function of deoxymyoglobin: oxygen sensor and regulator of cardiac energetics and function Circ Res 2007 100 1749 1754 17495223
- [147]Godber BLJ Doel JJ Sapkota GP Blake DR Stevens CR Eisenthal R Harrison R Reduction of Nitrite to Nitric Oxide Catalyzed by Xanthine Oxidoreductase J Biol Chem 2000 275 7757 7763 10713088
- [211]Nohl H Staniek K Kozlov AV The existence and significance of a mitochondrial nitrite reductase Redox Rep 2005 10 281 286 16438799
- Authors
- van Faassen, E. E., Bahrami, S., Feelisch, M., Hogg, N., Kelm, M., Kim‐Shapiro, D. B., Kozlov, A. V., Li, H., Lundberg, J. O., Mason, R., Nohl, H., Rassaf, T., Samouilov, A., Slama‐Schwok, A., Shiva, S., Vanin, A. F., Weitzberg, E., Zweier, J., & Gladwin, M. T.
- Affiliations
- Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA (AT)
- University of Warwick (GB)
- Medical College of Wisconsin (US)
- Universitätsklinikum Aachen (DE)
- Wake Forest University (US)
- The Ohio State University (US)
- Karolinska Institutet (SE)
- National Institute of Environmental Health Sciences (US)
- University of Veterinary Medicine Vienna (AT)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- National Institutes of Health (US)
- Russian Academy of Sciences (RU)
- University of Pittsburgh Medical Center (US)
- ORCID
- Venue
- Medicinal Research Reviews
- Publisher
- Wiley
- Published
- 2009-02-13
- Volume
- 29
- Issue
- 5
- Pages
- 683-741
- ISSN
- 0198-6325 (ISSN-L)
- 1098-1128
- PMC
- PMC2725214
- OpenAlex
- W2130121105
- Cited by
- 435
- References
- 271
- Citations by year
- 2026: 14 · 2025: 19 · 2024: 17 · 2023: 16 · 2022: 15 · 2021: 16 · 2020: 18 · 2019: 14 · 2018: 30 · 2017: 33 · 2016: 29 · 2015: 26 · 2014: 35 · 2013: 31 · 2012: 36
- FWCI
- 4.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Medicinal Research Reviews (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R29HL058091, HL058091, HL05891, K02HL078706, R37HL058091, HL078706, R01HL058091)
- National Institute of General Medical Sciences (R29GM055792, GM55792, R01GM055792)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- nitrite, hypoxia, hypoxia signaling, nitric oxide, nitrate, vasodilation, mitochondrial respiration, oxygen gradients, nitrite reductase
- MeSH terms
- Animals, Hypoxia, Humans, Nitrates, Nitric Oxide, Nitrites, Oxidation-Reduction, Oxygen, Vasodilation, Signal Transduction, Reperfusion Injury, Rats, Nitric Oxide Synthase Type III
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