Characterization of the Mechanism and Magnitude of Cytoglobin-mediated Nitrite Reduction and Nitric Oxide Generation under Anaerobic Conditions
Open accessAbstract
Cytoglobin (Cygb) is a recently discovered cytoplasmic heme-binding globin. Although multiple hemeproteins have been reported to function as nitrite reductases in mammalian cells, it is unknown whether Cygb can also reduce nitrite to nitric oxide (NO). The mechanism, magnitude, and quantitative importance of Cygb-mediated nitrite reduction in tissues have not been reported. To investigate this pathway and its quantitative importance, EPR spectroscopy, spectrophotometric measurements, and chemiluminescence NO analyzer studies were performed. Under anaerobic conditions, mixing nitrite with ferrous-Cygb triggered NO formation that was trapped and detected using EPR spin trapping. Spectrophotometric studies revealed that nitrite binding to ferrous-Cygb is followed by formation of ferric-Cygb and NO. The kinetics and magnitude of Cygb-mediated NO formation were characterized. It was observed that Cygb-mediated NO generation increased linearly with the increase of nitrite concentration under anaerobic conditions. This Cygb-mediated NO production greatly increased with acidosis and near-anoxia as occur in ischemic conditions. With the addition of nitrite, soluble guanylyl cyclase activation was significantly higher in normal smooth muscle cells compared with Cygb knocked down cells with Cygb accounting for ∼40% of the activation in control cells and ∼60% in cells subjected to hypoxia for 48 h. Overall, these studies show that Cygb-mediated nitrite reduction can play an important role in NO generation and soluble guanylyl cyclase activation under hypoxic conditions, with this process regulated by pH, oxygen tension, nitrite concentration, and the redox state of the cells.
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Excess superoxide or other ROS in the cell causes modification of different parts of the cellular machinery and is a known player in the genesis and progression of cardiovascular disease.
“The excess of superoxide, or other ROS, in the cell causes the modification of different parts of the cellular machinery and is a known player in the genesis and progression of cardiovascular disease (227, 408, 409, 570, 672, 700, 893).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [570]
Uncoupling of eNOS has been noted as a target for therapeutic potential.
“As such, the uncoupling of eNOS has been noted as a target for therapeutic potential (488, 569, 570, 600, 784).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [570]
Increased ROS eventually causes eNOS uncoupling via BH4 depletion, Zn/S cluster breakdown, and other routes, further perpetuating the generation of superoxide and other ROS.
“As discussed in previous section, increased ROS eventually causes eNOS uncoupling via BH4 depletion, Zn/S cluster breakdown, and other routes, further perpetuating the generation of superoxide and other ROS (FIGURE 17) (488, 570).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [570]
Cytoglobin is another hexacoordinate hemoprotein that can reduce nitrite following a similar mechanism as Ngb.
“Cytoglobin is another hexacoordinate hemoprotein that can reduce nitrite following a similar mechanism as Ngb [74].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [74]
The rate constant for cytoglobin-mediated nitrite reduction was measured to be about 0.14 M−1s−1 (pH 7, 25°C) and NO production rates were estimated to be capable of reaching 0.35 nM/s under physiologically-relevant hypoxia and acidosis.
“The rate constant was measured to be about 0.14 M−1s−1 (pH 7, 25°C and NO production rates were estimated to be capable of reaching 0.35 nM/s under physiologically-relevant hypoxia and acidosis [74].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [74]
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- Authors
- Li, H., Hemann, C., Abdelghany, T. M., El-Mahdy, M. A., & Zweier, J. L.
- Affiliations
- The Ohio State University (US)
- Corresponding author
- Zweier, Jay L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 287
- Issue
- 43
- Pages
- 36623-36633
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3476328
- OpenAlex
- W2066546505
- Cited by
- 132
- References
- 50
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 13 · 2022: 6 · 2021: 8 · 2020: 10 · 2019: 7 · 2018: 14 · 2017: 12 · 2016: 8 · 2015: 12 · 2014: 14 · 2013: 15 · 2012: 3
- FWCI
- 6.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-38324, R01HL063744, HL 65608, P01HL065608, HL 63744, R01HL038324)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Keywords
- nitrite reduction, nitric oxide production, anaerobic conditions, hypoxia, acidosis, oxygen partial pressure, smooth muscle cells, ischemia
- MeSH terms
- Cytoglobin, Anaerobiosis, Cells, Cultured, Electron Spin Resonance Spectroscopy, Globins, Guanylate Cyclase, Humans, Hydrogen-Ion Concentration, Kinetics, Luminescent Measurements, Nitric Oxide, Nitrites, Oxidation-Reduction, Oxygen, Cell Hypoxia, Myocytes, Smooth Muscle
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