Isoform-specific differences in the nitrite reductase activity of nitric oxide synthases under hypoxia
Open accessAbstract
Nitrite (NO(2)(-)) recycling to nitric oxide (NO) is catalysed by a number of enzymes and induces a protective vasodilation effect under hypoxia/ischaemia. In the present work, we tested the in vitro ability of the three NOS (nitric oxide synthase) isoforms to release NO from nitrite under anoxia using electrochemical detection, chemiluminescence and absorption spectroscopy. The release of free NO from anoxic nitrite solutions at 15 muM was specific to the endothelial NOS isoform (eNOS) and did not occur with the neuronal (nNOS) or inducible (iNOS) isoforms. Unlike xanthine oxidase, the eNOS reductase domain did not recycle nitrite to NO, and wild-type eNOS did not reduce nitrate. Our data suggest that structural and, by inference, dynamic differences between nNOS and eNOS in the distal haem side account for eNOS being the only isoform capable of converting nitrite into NO at pH 7.6. In human dermal microvascular endothelial cells under careful control of oxygen tension, the rates of NO formation determined by chemiluminescence were enhanced approximately 3.6- and approximately 8.3-fold under hypoxia (2 p.p.m. O(2)) and anoxia (argon) respectively compared with normoxia ( approximately 22 p.p.m. O(2)) using 10 muM extracellular nitrite. NOS inhibitors inhibited this hypoxic NO release. Our data show that eNOS is unique in that it releases NO under all oxygen levels from normoxia to complete anoxia at physiological micromolar nitrite concentrations. The magnitude of the hypoxic NO release by the endothelial cells suggest that the endothelium could provide an appropriate response to acute episodic ischaemia and may explain the observed eNOS-expression-specific protective effect as a short-term response in animal models of acute hypoxia.
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Endothelial NOS is the only NOS isoform that is capable of effectively reducing nitrite and it does so at a rate of 3.5 nM/sec per micromolar protein.
“Slama-Schwok and colleagues showed that endothelial NOS is the only NOS isoform that is capable of effectively reducing nitrite and it does so at a rate of 3.5 nM/sec per micromolar protein [83].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [83]
Endothelial NOS has been shown to be capable of reducing nitrite to NO.
“Endothelial NOS has also been shown to be capable of reducing nitrite to NO [81–83].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [83]
The calculated eNOS-mediated nitrite reduction rate is not consistent with the reported observation that the rate of NO production from endothelial cells in the presence of 10 mM nitrite actually increases 4-fold in hypoxia and 8-fold in anoxia.
“This calculated value is not consistent with the reported observation that the rate NO production from endothelial cells in the presence of 10 mM nitrite actually increases 4-fold in hypoxia and 8-fold in anoxia [83].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [83]
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Nitrite as Regulator of Hypoxic Signaling in Mammalian Physiology
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“…transfer, resulting in the oxidation of Mo (IV) to Mo (V) [68,69]. through electron transfer, resulting in the oxidation of Mo (IV) to Some of these enzymes are upregulated under hypoxic conditions, when there is an increased demand for NO formation and improved blood flow (Figure 2) [70,71].”
BackgroundAdhikari, H., Patel, P., Javvaji, N., Crabtree, M. J., & Simon, J. N. (2025) · The Journal of Cardiovascular Aging · doi:10.20517/jca.2025.14 · Cited by 10 · see citing works
“Rather, the oxygenase domain of eNOS serves as a location for nitrite reduction [57,58] and maintains NO levels to sustain vasodilation.”
Galinato, M. G. I., Fogle, R. S., Stetz, A., & Galan, J. F. (2015) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2015.10.010 · Cited by 8 · see citing works
Wang, L., Almeida, L. E. F., Kamimura, S., van der Meulen, J. H., Nagaraju, K., Quezado, M., Wakim, P., & Quezado, Z. (2018) · Nitric Oxide · doi:10.1016/j.niox.2018.08.005 · Cited by 7 · see citing works
“Researchers have shown that nitrite can be reduced into NO by a number of enzymes including deoxyhemoglobin, xanthine oxidoreductase (XOR), and nitric oxide synthase (NOS) among others[70; 71; 72; 73].”
BackgroundHung, C.-C., Yabushita, A., Kobayashi, T., Chen, P.-F., & Liang, K. S. (2017) · Chemical Physics Letters · doi:10.1016/j.cplett.2017.04.081 · Cited by 7 · see citing works
Heme Protein Metabolism of NO and Nitrite
Kim‐Shapiro, D. B., & Gladwin, M. T. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-804273-1.00006-5 · Cited by 5 · see citing works
Allergic activation of mast cells.
Parker, C. W. (1986) · PubMed · Cited by 5 · see citing works
The catalytic mechanism for NO production by the mitochondrial enzyme, sulfite oxidase
Mutus, B. (2019) · Biochemical Journal · doi:10.1042/bcj20190338 · Cited by 4 · see citing works
Brain acute ischemia mechanisms: implications to experimental and clinical treatment
Ivanov, E. V., Gavrilova, S. A., & Кошелев, В. Б. (2021) · Regional blood circulation and microcirculation · doi:10.24884/1682-6655-2021-20-2-5-19 · Cited by 4 · see citing works
Kumar, S., Barthwal, M. K., & Dikshit, M. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.177444 · Cited by 3 · see citing works
“Moreover, cytochrome c and nitric-oxide synthases have been found to possess nitrite reductase activity (Basu et al., 2008; Mikula et al., 2009).”
BackgroundUltrafast Transient Absorption Spectroscopy for Probing Primary Photochemical Reaction of Proteins
Yabushita, A. (2024) · Springer eBooks · doi:10.1007/978-981-97-2914-2_11 · Cited by 2 · see citing works
Hung, C.-C., Yabushita, A., Kobayashi, T., Chen, P.-F., & Liang, K. S. (2016) · Biophysical Chemistry · doi:10.1016/j.bpc.2016.05.001 · Cited by 2 · see citing works
Protective Role of Nitrate/Nitrite Reductase System during Transient Global Cerebral Ischemia
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“Under these conditions, several enzymes catalyze the opposite reaction, for example deoxyhemoglobin and NOS act as nitrite reductases [12].”
BackgroundLee, J. W., Hwang, E. T., & Han, J. S. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/5514537 · Cited by 2 · see citing works
“The synthesis of NO from L-arginine is catalyzed by three nitric oxide synthase isoforms via an oxygen-consuming pathway, which might be prohibited under conditions of low oxygen tension [17].”
BackgroundNitric Oxide and Genomic Stability
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“That NOS activity and NO/RNS generations are stimulated under certain hypoxic conditions [49–51] suggest that some pro-carcinogenic effects of hypoxic microenvironment are also NO/RNS- dependent.”
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“as data shows that only eNOS releases NO• across the entire oxygen gradient from normoxia to complete anoxia (Mikula et al. 2009).”
Background
- Authors
- Mikula, I., Durocher, S., Martasek, P., Mutus, B., & Slama-Schwok, A.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- University of Windsor (CA)
- Department of Pediatrics and Center for Genomics, First School of Medicine, Charles University of Prague, Prague, Czech Republic
- Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, ON, Canada, N9B 3P4
- Laboratory for Optics and Biosciences, INSERM U696, CNRS UMR7645, Ecole Polytechnique, 91128 Palaiseau, France
- ORCID
- Mikula, Ivan
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2009-02-25
- Volume
- 418
- Issue
- 3
- Pages
- 673-682
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2016646182
- Cited by
- 51
- References
- 53
- Citations by year
- 2025: 2 · 2024: 3 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 4 · 2013: 4 · 2012: 3
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion, other-oa)
- Funders
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- nitric oxide synthase, nitrite reductase activity, endothelial nitric oxide synthase, neuronal nitric oxide synthase, inducible nitric oxide synthase, hypoxia, anoxia, ischemia, dermal microvascular endothelial cells, nitric oxide synthase inhibitors, vasodilation
- MeSH terms
- Hypoxia, Nitrite Reductases, Nitrites, Endothelial Cells, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type III
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