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
Cosby, K., Partovi, K. S., Crawford, J. H., Patel, R. P., Reiter, C. D., Martyr, S., Yang, B. K., Waclawiw, M. A., Zalos, G., Xu, X., et al. (2003) · Nature Medicine · doi:10.1038/nm954 · Cited by 1,807
Self-citationEnzyme-independent formation of nitric oxide in biological tissues
Zweier, J. L., Wang, P., Samouilov, A., & Kuppusamy, P. (1995) · Nature Medicine · doi:10.1038/nm0895-804 · Cited by 788
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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Lundberg, J. O., & Weitzberg, E. (2022) · Cell · doi:10.1016/j.cell.2022.06.010 · Cited by 879
Nitric oxide signalling in cardiovascular health and disease
Farah, C., Michel, L. Y. M., & Balligand, J.-L. (2018) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2017.224 · Cited by 779
Nitrate and nitrite in biology, nutrition and therapeutics
Lundberg, J. O., Gladwin, M. T., Ahluwalia, A., Benjamin, N., Bryan, N. S., Butler, A., Cabrales, P., Fago, A., Feelisch, M., Ford, P. C., et al. (2009) · Nature Chemical Biology · doi:10.1038/nchembio.260 · Cited by 617
Self-citationStrategies to increase nitric oxide signalling in cardiovascular disease
Lundberg, J. O., Gladwin, M. T., & Weitzberg, E. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4623 · Cited by 576
Self-citationNitrite as Regulator of Hypoxic Signaling in Mammalian Physiology
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., et al. (2009) · Medicinal Research Reviews · doi:10.1002/med.20151 · Cited by 435
Self-citation
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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