Nitrite Reductase Function of Deoxymyoglobin: Oxygen Sensor and Regulator of Cardiac Energetics and Function
Abstract
Although the primary function of myoglobin (Mb) has been considered to be cellular oxygen storage and supply, recent studies have suggested to classify Mb as a multifunctional allosteric enzyme. In the heart, Mb acts as a potent scavenger of nitric oxide (NO) and contributes to the attenuation of oxidative damage. Here we report that a dynamic cycle exists in which a decrease in tissue oxygen tension drives the conversion of Mb from being an NO scavenger in normoxia to an NO producer in hypoxia. The NO generated by reaction of deoxygenated Mb with nitrite is functionally relevant and leads to a downregulation of cardiac energy status, which was not observed in mice lacking Mb. As a consequence, myocardial oxygen consumption is reduced and cardiac contractility is dampened in wild-type mice. We propose that this pathway represents a novel homeostatic mechanism by which a mismatch between oxygen supply and demand in muscle is translated into the fractional increase of deoxygenated Mb exhibiting enhanced nitrite reductase activity. Thus, Mb may act as an oxygen sensor which through NO can adjust muscle energetics to limited oxygen supply.
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The peptide prevents NOX1 assembly and does not inhibit NOX2, NOX4, or NOX5 as tested in in vitro assays.
“The peptide prevents NOX1 assembly and does not inhibit NOX2, NOX4, or NOX5 as tested in in vitro assays (772, 792).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [772]
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 [99]
Administration of nitrite under hypoxia regulates cardiac energetics and functions resembling acute hibernation.
“We have recently shown that the administration of nitrite under hypoxia regulates cardiac energetics and functions resembling the characteristics described for acute hibernation.28”
From Dietary nitrate supplementation improves revascularization in chronic ischemia (2012) · cites this paper as [28]
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 [53]
Exogenous administration of nitrite correlates with increased levels of S-nitrosothiols in red blood cells and other tissues both in vivo and in vitro.
“exogenous administration of nitrite correlates with increased levels of S-nitrosothiols in red blood cells and other tissues both in vivo and in vitro [25, 43, 46-53].”
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 [53]
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 [113]
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- Authors
- Rassaf, T., Flögel, U., Drexhage, C., Hendgen-Cotta, U., Kelm, M., & Schrader, J.
- Affiliations
- Universitätsklinikum Aachen (DE)
- From the University Hospital Aachen, Department of Medicine, Division of Cardiology, Pulmonary and Vascular Diseases (T.R., C.D., U.H.-C., M.K.), Aachen; and the Department of Cardiovascular Physiology (U.F., J.S.), Heinrich-Heine-University Düsseldorf, Germany.
- Venue
- Circulation Research
- Published
- 2007-06-22
- Volume
- 100
- Issue
- 12
- Pages
- 1749-1754
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2104194825
- Cited by
- 284
- References
- 32
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 15 · 2020: 9 · 2019: 10 · 2018: 7 · 2017: 17 · 2016: 11 · 2015: 19 · 2014: 21 · 2013: 29 · 2012: 28
- FWCI
- 10.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- 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
- myoglobin, nitrite reductase activity, nitric oxide, nitrite, hypoxia, oxygen sensing, myocardial energy metabolism, myocardial oxygen consumption, cardiac contractility, oxygen supply and demand, allosteric enzymes, oxidative damage
- MeSH terms
- Animals, Energy Metabolism, Heart, Homeostasis, Myocardium, Myoglobin, Nitric Oxide, Nitrite Reductases, Oxygen, Oxygen Consumption, Mice, Knockout, Mice
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