Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury
Open accessAbstract
The nitrite anion is reduced to nitric oxide (NO*) as oxygen tension decreases. Whereas this pathway modulates hypoxic NO* signaling and mitochondrial respiration and limits myocardial infarction in mammalian species, the pathways to nitrite bioactivation remain uncertain. Studies suggest that hemoglobin and myoglobin may subserve a fundamental physiological function as hypoxia dependent nitrite reductases. Using myoglobin wild-type ((+/+)) and knockout ((-/-)) mice, we here test the central role of myoglobin as a functional nitrite reductase that regulates hypoxic NO* generation, controls cellular respiration, and therefore confirms a cytoprotective response to cardiac ischemia-reperfusion (I/R) injury. We find that myoglobin is responsible for nitrite-dependent NO* generation and cardiomyocyte protein iron-nitrosylation. Nitrite reduction to NO* by myoglobin dynamically inhibits cellular respiration and limits reactive oxygen species generation and mitochondrial enzyme oxidative inactivation after I/R injury. In isolated myoglobin(+/+) but not in myoglobin(-/-) hearts, nitrite treatment resulted in an improved recovery of postischemic left ventricular developed pressure of 29%. In vivo administration of nitrite reduced myocardial infarction by 61% in myoglobin(+/+) mice, whereas in myoglobin(-/-) mice nitrite had no protective effects. These data support an emerging paradigm that myoglobin and the heme globin family subserve a critical function as an intrinsic nitrite reductase that regulates responses to cellular hypoxia and reoxygenation [corrected]
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Factors demonstrated to reduce nitrite in tissues include deoxyhemoglobin, deoxymyoglobin, xanthine oxidoreductase, heme-based enzymes in mitochondria, and acidosis during ischemia.
“There are a number of factors that have been demonstrated to reduce nitrite in the tissues, including deoxyhemoglobin, deoxymyoglobin, xanthine oxidoreductase, heme-based enzymes in the mitochondria and acidosis during ischemia [99,100].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [100]
A cytoprotective role of nitrite in myocardial, liver, kidney, and brain ischemia/reperfusion injury has previously been demonstrated.
“A cytoprotective role of nitrite in the setting of myocardial, liver, kidney, and brain ischemia/reperfusion injury has previously been demonstrated.19,29,30”
From Dietary nitrate supplementation improves revascularization in chronic ischemia (2012) · cites this paper as [19]
Mb-mediated nitrite reduction has been reported to be important in both cardiomyocytes and smooth muscle.
“Mb-mediated nitrite reduction has been reported to be important in both cardiomyocytes [55] and smooth muscle [56].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [55]
A functional role for myoglobin in nitrite reduction and signaling is strongly supported by multiple studies in myoglobin knockout mice showing a reduction in nitrite mediated effects on mitochondrial respiration, cardiac function, ischemia reperfusion cytoprotection, and systemic hypoxic vasodilation.
“As discussed below, a functional role for myoglobin in nitrite reduction and signaling is strongly supported by multiple studies in myoglobin knockout mice showing a reduction in nitrite mediated effects on mitochondrial respiration, cardiac function, ischemia reperfusion cytoprotection, and systemic hypoxic vasodilation [54–56].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [55]
Low concentrations of nitrite mediate cytoprotection in a variety of tissues in animal models including heart, liver, brain, kidney, hindlimb, and human forearm.
“The efficacy of low concentrations of nitrite in mediating cytoprotection has been demonstrated in a variety of tissues in animal models including heart [8, 9, 55, 118–122] liver [9, 120, 123], brain [124–126], kidney [127, 128], hindlimb [129], and human forearm [23].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [55]
In vivo, nitrite administration reduced infarct size from myocardial infarction by 61% in wild type mice.
“This Mb-dependent effect was also demonstrated in vivo where nitrite administration reduced infract size from myocardial infarction by 61% in wild type mice”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [55]
Administration of nitrite decreased infarct size in wild type hearts by 36% when subject to IR.
“whereas administration of nitrite decreased infarct size in wild type hearts by 36% when subject to IR”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [55]
Perfused hearts from wild type mice produced about twice as much NO from nitrite as knockouts ex vivo when subject to ischemia.
“Perfused hearts from wild type mice produced about twice as much NO from nitrite as knockouts ex vivo when subject to ischemia [55].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [55]
In vivo, nitrite had no effect on infarct size in Mb knockout mice.
“and nitrite had no effect in knockout mice [55].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [55]
Nitrite had no effect on infarct size in hearts from Mb knockout mice subject to IR.
“nitrite had no effect on infarct size on heats from knockouts [55].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [55]
Evidence that myoglobin/nitrite interactions can promote NO-signaling in the context of an ischemic insult to the heart has been established using multiple criteria including myoglobin knockout mice.
“evidence that myoglobin/nitrite interactions can promote NO-signaling in the context of an ischemic insult to the heart has been established using multiple criteria including the use of myoglobin knockout mice [28, 33, 53, 60].”
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 [33]
Protection afforded by nitrite administration in a model of cardiac ischemia-reperfusion is lost in myoglobin knockout mice and coincides with loss of NO formation detected by EPR.
“protection afforded by nitrite administration in a model of ischemia-reperfusion in the heart is lost when myoglobin knock-out mice are used instead of wild type animals and this coincides with a loss of NO formation detected by EPR [33].”
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 [33]
Nitrite-induced S-nitrosation of complex I of the electron transport chain decreases mitochondrial reactive species formation and subsequently confers protection against ischemia-reperfusion injury.
“the nitrite-induced S-nitrosation of complex I of the electron transport chain which decreases mitochondrial reactive species formation and subsequently confers protection against ischemia-reperfusion injury [104] [33, 86, 105, 106].”
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 [33]
Genetic deletion of myoglobin in the heart significantly diminished the protective effect of sodium nitrite on myocardial ischemia-reperfusion.
“In these studies, genetic deletion of myoglobin in the heart significantly diminished the protective effect of sodium nitrite on myocardial ischemia-reperfusion [113, 114].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [114]
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- Authors
- Hendgen-Cotta, U. B., Merx, M. W., Shiva, S., Schmitz, J., Becher, S., Klare, J. P., Steinhoff, H.-J., Goedecke, A., Schrader, J., Gladwin, M. T., Kelm, M., & Rassaf, T.
- Affiliations
- Universitätsklinikum Aachen (DE)
- National Institutes of Health (US)
- Osnabrück University (DE)
- Heinrich Heine University Düsseldorf (DE)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-07-22
- Volume
- 105
- Issue
- 29
- Pages
- 10256-10261
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2481313
- OpenAlex
- W2096118264
- Cited by
- 418
- References
- 41
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 14 · 2023: 12 · 2022: 13 · 2021: 14 · 2020: 12 · 2019: 23 · 2018: 15 · 2017: 23 · 2016: 27 · 2015: 36 · 2014: 30 · 2013: 35 · 2012: 46
- FWCI
- 13.58
- Type
- journal article
- Language
- en
- Update notices
- correction (2008-08-26)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- myoglobin, nitrite reductase, nitric oxide, myocardial ischemia-reperfusion injury, hypoxia, cellular respiration, reactive oxygen species, cardioprotection, myocardial infarction, nitrite
- MeSH terms
- Aconitate Hydratase, Animals, Cell Survival, Heme, Male, Mitochondria, Heart, Myocardial Infarction, Myocardium, Myoglobin, Nitric Oxide, Nitrites, Oxidation-Reduction, Myocardial Reperfusion Injury, Reactive Oxygen Species, Mice, Knockout, Ventricular Dysfunction, Left, Cell Respiration, Nitrate Reductase, Mice, In Vitro Techniques
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