The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
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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In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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 the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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 the citing paper
“and nitrite had no effect in knockout mice [55].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [55]
In the citing paper
“nitrite had no effect on infarct size on heats from knockouts [55].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [55]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
Citations
Cites
Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation
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Self-citationEnzyme-independent formation of nitric oxide in biological tissues
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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 7×
“The application of 48 nmol sodium nitrite (50 l) into the left ventricular cavity occurred 5 min before reperfusion (16).”
BackgroundMethodInfluentialSelf-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 6×
“Recent studies have established a nitrite-induced reduction of infarct size in I/R (11, 16) and amelioration of cardiac function in murine hearts.”
BackgroundInfluentialRegulation of mitochondrial respiration by nitric oxide inhibition of cytochrome c oxidase
Brown, G. C. (2001) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(00)00238-3 · Cited by 602
Bolli, R. (2001) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.2001.1462 · Cited by 601
Shiva, S., Huang, Z., Grubina, R., Sun, J., Ringwood, L. A., MacArthur, P. H., Xu, X., Murphy, E., Darley-Usmar, V. M., & Gladwin, M. T. (2007) · Circulation Research · doi:10.1161/01.res.0000260171.52224.6b · Cited by 599
Self-citationShiva, S., Sack, M. N., Greer, J. J., Duranski, M., Ringwood, L. A., Burwell, L., Wang, X., MacArthur, P. H., Shoja, A., Raghavachari, N., et al. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20070198 · Cited by 555
Self-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
- 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 › Biochemistry › Hemoglobin structure and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Physiology (medical) › 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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