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Role of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics
Open accessAbstract
The anion nitrite (NO(2)(-)) constitutes a biochemical reservoir for nitric oxide (NO). Nitrite reduction to NO may be catalyzed by hemoglobin, myoglobin or other metal-containing enzymes and occurs at increasing rates under conditions of physiologic hypoxia or ischemia. A number of laboratories have now demonstrated in animal models the ability of nitrite to provide potent cytoprotection following focal ischemia-reperfusion (IR) injury of the heart, liver, brain, and kidney. While the mechanism of nitrite-mediated cytoprotection remains to be fully characterized, the release of nitrite-derived NO following IR appears to be central to this mechanism. The evidence of nitrite-mediated cytoprotection against IR injury in multiple animal models opens the door to potential therapeutic opportunities in human disease. Here we review the mechanisms for nitrite formation in blood and tissue, its metabolic equilibrium with NO, nitrate, and NO-modified proteins, the evidence supporting nitrite-mediated cytoprotection, and the potential mechanisms driving cytoprotection, and we explore the opportunities for the therapeutic application of nitrite for human disease.
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“Nitrite administered before or during cardiac ischemia has been shown to protect cardiac function and attenuate infarct size in a number of small and large animal models (226, 374, 864).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [226]
In the citing paper
“Nitrite is a dietary constituent that protects the heart against I/R injury in many animal models during both ischemia and preconditioning stage [186,187,188,189,190,191,192].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [189]
In the citing paper
“relevant biological effects were associated with nitrite or nitrate, including beneficial effects against ischemia-reperfusion injury [11,18,19], vasorelaxant properties [20], pulmonary vasodilator effects [21][22][23], and antihypertensive effects in experimental [24][25][26][27] and in clinical studies [28][29][30].”
From Sodium nitrite downregulates vascular NADPH oxidase and exerts antihypertensive effects in hypertension (2011) · cites this paper as [19]
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Andreadou, I., Iliodromitis, E. K., Rassaf, T., Schulz, R., Papapetropoulos, A., & Ferdinandy, P. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12811 · Cited by 213
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“Furthermore, the mouse model of liver I/R has been especially informative in demonstrating that endogenous or exogenous NO protects the liver from post-ischemic injury by normalizing the redox potential of the liver, attenuating the transcriptional activation of a number of injurious and pro-inflammatory genes, limiti…”
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“Interestingly, there is consistent evidence that this compound has potent cytoprotective properties, especially in IR injury (29, 72, 148), potentially mediated by nitrosative inhibition of mitochondrial respiratory chain I, which causes a reduced ROS production at reperfusion.”
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“The reduction of nitrite to NO has been cited to occur in a variety of biological tissues and has been prominently featured in protection against ischemic injury (32).”
BackgroundImpact of hypoxic hepatitis on mortality in the intensive care unit
Fuhrmann, V., Kneidinger, N., Herkner, H., Heinz, G., Nikfardjam, M., Bojic, A., Schellongowski, P., Angermayr, B., Schöniger–Hekele, M., Madl, C., et al. (2011) · Intensive Care Medicine · doi:10.1007/s00134-011-2248-7 · Cited by 137
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Self-citationNitrite mediates cytoprotection after ischemia/reperfusion by modulating mitochondrial function
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“The ability of nitrite to decrease infarct size has now been recapitulated by a number of other investigators in both in vivo and in vitro models of cardiac I/R (Table 1). Remarkably, the dose response of nitrite is highly reproducible across these studies, with the administration of 48 nmol (which increases plasma ni…”
BackgroundInfluentialSelf-citationMitochondria as metabolizers and targets of nitrite
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“Moreover, this phenomenon was absent in experiments in which the myoglobin was oxi- dized or in which the NO scavenger PTIO (2-phenyl-4,4,5,5tetramethylimidazoline-3-oxide-1-oxyl) was present, confirming that the inhibition of respiration under these conditions was indeed due to an interaction of nitrite and myoglobin…”
Self-citationRegulation of mitochondrial function and energetics by reactive nitrogen oxides
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δ-Opioid receptor activation attenuates oxidative injury in the ischemic rat brain
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Nitrite reduction by molybdoenzymes: a new class of nitric oxide-forming nitrite reductases
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“Although the NO effect is mainly compartmentalized, emerging evidence suggests that NO generated at one compartment can be converted to inert NO metabolites such as nitrite and nitrate and transferred to other compartment and then reduced back to NO in the presence of myoglobin (101).”
Myocardial protection by nitrite
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“NO can also exert its cytoprotective role by inhibiting caspase through S-nitrosation and via cGMP to avoid the release of cytochrome c from mitochondria, thus preventing apoptosis (91).”
InfluentialBice, J. S., Jones, B. R., Chamberlain, G. R., & Baxter, G. F. (2016) · Basic Research in Cardiology · doi:10.1007/s00395-016-0540-y · Cited by 72
“…NO have given rise to a multitude of experimental and clinical studies focusing on the delivery of exogenous NO, in the form of various NO species and NO-donor compounds, to limit ischemia/reperfusion injury [7] with the general hypothesis being that NO ameliorates ischemia/reperfusion injury.”
A Review of the Pathophysiology and Novel Treatments for Erectile Dysfunction
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“[99] C.”
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“Nitrite has protective effects in different ischemia reperfusion injury models (19).”
BackgroundNO2– Activation and Reduction to NO by a Nonheme Fe(NO2)2 Complex
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“Both nitrate and nitrite have therapeutic effects in animal models of ischemia–reperfusion injury [27,28], reduced cellular oxygen consumption [29], reversal of metabolic syndrome, reduced oxidative stress [30], and protection against gastric ulcerations [31,32].”
Heme/Copper Assembly Mediated Nitrite and Nitric Oxide Interconversion
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“Nitrite therapy has received much attention in recent years as a cytoprotective therapy in ischemia/reperfusion injury or disease states associated with NO deficiency [41,42].”
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“Mechanistically, the reduction of NO2 to NO is thought to be the initial step in a number of vascular responses that NO2 mediates in vivo, including stimulation of angiogenesis [21], protection from ischemia/reperfusion injury [22-25] and reversal of intimal hyperplasia after vascular injury [26].”
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“However, more nitrite reducing pathways are available under ischaemic/hypoxic conditions (for review, see Dezfulian et al., 2007; Sinha et al., 2008; Shiva et al., 2011; Tota et al., 2011).”
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“NO can also reduce mitochondrial ROS through direct inhibition of complex I during ischemia thereby minimizing ROS production at reperfusion [36].”
BackgroundPharmacology and therapeutic role of inorganic nitrite and nitrate in vasodilatation
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“…groups that nitrite-derived bioactivity is cardioprotective by minimising cell death by apoptosis (Webb et al., 2004; Duranski et al., 2005; Dezfulian et al., 2007; Shiva et al., 2007a, 2007b; Tripatara et al., 2007), exerts anti-aggregatory effects (Srihirun et al., 2012; Corti et al.,…”
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“The potential for nitrite to be an hypoxic source for NO has also opened the door for nitrite therapeutics for various conditions characterized by ischemic injury, the pathogenesis of which is mediated in part by a loss of NO-signaling as exemplified by ischemia-reperfusion injury [8-11].”
Kemmner, S., Lorenz, G., Wobst, J., Kessler, T., Wen, M., Günthner, R., Stock, K., Heemann, U., Burkhardt, K., Baumann, M., et al. (2017) · Nitric Oxide · doi:10.1016/j.niox.2017.01.011 · Cited by 74
Inhaled nitric oxide: Current clinical concepts
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“Several studies have shown that exogenously administrated nitrite limits tissue damage during ischemia-reperfusion events in mammalian models (18, 63), and nitrite is currently being tested as a therapeutic agent against various cardiovascular problems (5, 48).”
BackgroundActivation of Hypoxia Response in Endothelial Cells Contributes to Ischemic Cardioprotection
Kerkelä, R., Karsikas, S., Szabó, Z., Serpi, R., Magga, J. M., Gao, E., Alitalo, K. K., Anisimov, A., Sormunen, R. T., Pietilä, I., et al. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00432-13 · Cited by 55
“NO is known to mediate several beneficial effects promoting cardiac ischemia survival (29).”
BackgroundMaia, L. B., & Moura, J. J. G. (2018) · Redox Biology · doi:10.1016/j.redox.2018.08.020 · Cited by 57
McArthur, J. G., Svenstrup, N., Chen, C., Fricot, A., Carvalho, C., Nguyen, J., Nguyen, P., Parachikova, A. I., Abdulla, F. A., Vercellotti, G. M., et al. (2019) · Haematologica · doi:10.3324/haematol.2018.213462 · Cited by 56
“Red cell lysis results in the release of Hb which consumes the plasma pool of NO and increases the vasculopathy associated with SCD7 nitrite generated in the plasma from an excess of NO produced by endothelial NO synthase (eNOS), can be converted back to NO as levels drop, acting as a biochemical reserve for NO.47 In…”
BackgroundInfluentialApelin/APJ System: A Novel Therapeutic Target for Myocardial Ischemia/Reperfusion Injury
Chen, Z., Wu, D., Li, L., & Chen, L. (2016) · DNA and Cell Biology · doi:10.1089/dna.2016.3391 · Cited by 53
“Nitrite reduction to NO may be catalyzed by myoglobin, hemoglobin, or other metal-containing enzymes and occurs at increasing rates under conditions of physiologic hypoxia or ischemia (Dezfulian et al. , 2007).”
Nitrite therapy is neuroprotective and safe in cardiac arrest survivors
Dezfulian, C., Alekseyenko, A., Dave, K. R., Raval, A. P., Do, R., Kim, F., & Pérez‐Pinzón, M. A. (2012) · Nitric Oxide · doi:10.1016/j.niox.2012.03.007 · Cited by 51
“In less than a decade nitrite therapy has been demonstrated to mitigate reperfusion injury in multiple animal models of ischemiareperfusion in a variety of organs [14,15].”
BackgroundSelf-citationMitigation of chlorine gas lung injury in rats by postexposure administration of sodium nitrite
Yadav, A. K., Doran, S. F., Samal, A. A., Sharma, R., Vedagiri, K., Postlethwait, E. M., Squadrito, G. L., Fanucchi, M. V., Roberts, L. J., Patel, R. P., et al. (2010) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00278.2010 · Cited by 50
“NO2 -mediated protection against inflammatory tissue injury is thought to occur primarily by its reduction to NO by reduced hemoglobin in hypoxic red blood cells, which in turn could affect ALI by several mechanisms, including modulation of leukocyte adhesion and infiltration, inhibition of endothelial/ epithelial cel…”
BackgroundDietary intake and bio-activation of nitrite and nitrate in newborn infants
Jones, J. A., Hopper, A. O., Power, G. G., & Blood, A. B. (2014) · Pediatric Research · doi:10.1038/pr.2014.168 · Cited by 50
“suggested that nitrite reduction to NO in acidic tissues exacerbates postischemic injury (65), nitrite has since been consistently shown in experimental animals to be protective against I/R injury in the heart, brain, liver, and kidney (29,68).”
Shiva, S., Rassaf, T., Patel, R. P., & Gladwin, M. T. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq327 · Cited by 48
Self-citationMartı́nez-Ruiz, A., & Lamas, S. (2008) · IUBMB Life · doi:10.1002/iub.144 · Cited by 46
Hepatocellular protection by nitric oxide or nitrite in ischemia and reperfusion injury
Abe, Y., Hines, I. N., Zibari, G. B., & Grisham, M. B. (2008) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2008.10.006 · Cited by 44
Gori, T., & Daiber, A. (2009) · American Journal of Cardiovascular Drugs · doi:10.1007/bf03256591 · Cited by 44
Pattillo, C. B., Bir, S. C., Rajaram, V., & Kevil, C. G. (2010) · Cardiovascular Research · doi:10.1093/cvr/cvq297 · Cited by 44
“The preponderance of studies have shown that beneficial effects of near physiological plasma concentrations (high nanomolar) of sodium nitrite therapy emanate from the reduction of nitrite back to NO as the NO scavengers carboxy-PTIO (2-phenyl-4,4,5,5,tetramethylimidazoline-1-oxyl-3-oxide) or cell free haemoglobin blu…”
BackgroundMechanistic characterization of nitrite‐mediated neuroprotection after experimental cardiac arrest
Dezfulian, C., Kenny, E., Lamade, A. M., Missé, A., Krehel, N. M., Croix, C. M. S., Kelley, E. E., Jackson, T. C., Uray, T., Rackley, J., et al. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13764 · Cited by 42
“As a result, nitrite generation of NO required for activation of sGC or S-nitrosation occurs selectively during ischemia-reperfusion (Dezfulian et al. 2007) making it a potential precision medicine therapy for CA.”
BackgroundSelf-citationLim, C. C., Bryan, N. S., Jain, M., Garcia-Saura, M. F., Fernandez, B. O., Sawyer, D. B., Handy, D. E., Loscalzo, J., Feelisch, M., & Liao, R. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00673.2009 · Cited by 44
Nitrite Reduces Acute Lung Injury and Improves Survival in a Rat Lung Transplantation Model
Sugimoto, R., Okamoto, T., Nakao, A., Zhan, J., Wang, Y., Kohmoto, J., Tokita, D., Farver, C. F., Tarpey, M. M., Billiar, T. R., et al. (2012) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2012.04169.x · Cited by 40
Self-citationRole of β-Adrenergic Receptors and Nitric Oxide Signaling in Exercise-Mediated Cardioprotection
Calvert, J. W., & Lefer, D. J. (2013) · Physiology · doi:10.1152/physiol.00011.2013 · Cited by 40
Singh, M., Arya, A., Kumar, R., Bhargava, K., & Sethy, N. K. (2012) · Nitric Oxide · doi:10.1016/j.niox.2011.12.002 · Cited by 38
Sinha, S. S., Shiva, S., & Gladwin, M. T. (2008) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2008.05.001 · Cited by 37
“…is its ability to mediate cytoprotection after ischemia-reperfusion (I/R) in a number of organs and species (Baker et al. 2007, Bryan et al. 2007, Dezfulian et al. 2007, Duranski et al. 2005, Gonzalez et al. 2008, Jung et al. 2006, Lu et al. 2005, Shiva et al. 2007b, Tripatara et al. 2007,…”
BackgroundSelf-citationSkeletal Muscle Nitrate as a Regulator of Systemic Nitric Oxide Homeostasis
Piknova, B., Schechter, A. N., Park, J. W., Vanhatalo, A., & Jones, A. M. (2021) · Exercise and Sport Sciences Reviews · doi:10.1249/jes.0000000000000272 · Cited by 38
Murata, I., Nozaki, R., Ooi, K., Ohtake, K., Kimura, S., Ueda, H., Nakano, G., Sonoda, K., Inoue, Y., Uchida, H., et al. (2012) · Journal of Trauma and Acute Care Surgery · doi:10.1097/ta.0b013e31824a76b5 · Cited by 33
“nitrite administered before or during reperfusion has been demonstrated to protect against I/R injury in a number of animal models of myocardial infarction, stroke, liver infarction, and renal I/R injury.(6) However, there has been so far no experimental evidence indicating the therapeutic consequences of nitrite admi…”
BackgroundHematian, S., Kenkel, I., Shubina, T. E., Dürr, M., Liu, J. J., Siegler, M. A., Ivanović‐Burmazović, I., & Karlin, K. D. (2015) · Journal of the American Chemical Society · doi:10.1021/jacs.5b02174 · Cited by 33
Hathazi, D., Scurtu, F., Bischin, C., Mot, A. C., Attia, A. A. A., Kongsted, J., & Silaghi-Dumitrescu, R. L. (2018) · Molecules · doi:10.3390/molecules23020350 · Cited by 32
Kovács, M., Kiss, A., Gönczi, M., Miskolczi, G., Seprényi, G., Kaszaki, J., Kohr, M. J., Murphy, E., & Végh, Á. (2015) · PLoS ONE · doi:10.1371/journal.pone.0122243 · Cited by 29
Silva, M. R., Correia, A. O., dos Santos, G. C. A., Parente, L. L. T., de Siqueira, K. P., Lima, D. G. S., Moura, J. A., Ribeiro, A. E. D. S., da Costa, R. O., Lucetti, D. L., et al. (2018) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2018.02.001 · Cited by 30
“The anion nitrite (NO2) is considered a biochemical reservoir for nitric oxide (NO), and nitrite reduction to NO occurs at increasing rates in brain ischemia (Dezfulian et al., 2007).”
BackgroundKelpke, S. S., Chen, B., Bradley, K. M., Teng, X., Chumley, P., Brandon, A., Yancey, B., Moore, B., Head, H., Viera, L., et al. (2012) · Kidney International · doi:10.1038/ki.2012.116 · Cited by 28
Heart Failure Management: The Present and the Future
Jameel, M. N., & Zhang, J. J. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2488 · Cited by 28
“NO and the NO-modified proteins and lipids then exert their downstream beneficial effects through the following mechanisms (38): 1.”
Emerging role of nitrite in myocardial protection
Lefer, D. J. (2009) · Archives of Pharmacal Research · doi:10.1007/s12272-009-1804-y · Cited by 27
Effect of Out-of-Hospital Sodium Nitrite on Survival to Hospital Admission After Cardiac Arrest
Kim, F., Maynard, C. C., Dezfulian, C., Sayre, M. R., Kudenchuk, P. J., Rea, T. D., Sampson, D., Olsufka, M., May, S. J., & Nichol, G. (2021) · JAMA · doi:10.1001/jama.2020.24326 · Cited by 26
Self-citationKato, G. J. (2008) · Hematology · doi:10.1182/asheducation-2008.1.186 · Cited by 27
Current Pharmacological Advances in the Treatment of Cardiac Arrest
Papastylianou, A., & Mentzelopoulos, S. D. (2011) · Emergency Medicine International · doi:10.1155/2012/815857 · Cited by 25
“Nitrite therapy limits cellular injury and apoptosis after ischemia and reperfusion (I/R).(116) It has been proven to be cytoprotective in numerous animal models of focal I/R injury, including rodent heart, brain, liver and kidney, canine heart, and primate brain.”
BackgroundDias-Junior, C. A., Cáu, S. B. D. A., & Tanus-Santos, J. E. (2008) · Jornal Brasileiro de Pneumologia · doi:10.1590/s1806-37132008000600012 · Cited by 26
Jones, J. A., Ninnis, J. R., Hopper, A. O., Ibrahim, Y., Merritt, T. A., Wan, K., Power, G. G., & Blood, A. B. (2013) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607113496118 · Cited by 24
Nanotechnology for Electroanalytical Biosensors of Reactive Oxygen and Nitrogen Species
Seenivasan, R., Kolodziej, C., Karunakaran, C., & Burda, C. (2017) · The Chemical Record · doi:10.1002/tcr.201600143 · Cited by 24
Nebulized nitrite protects rat lung grafts from ischemia reperfusion injury
Okamoto, T., Tang, X., Janocha, A., Farver, C. F., Gladwin, M. T., & McCurry, K. R. (2013) · The Journal of Thoracic and Cardiovascular Surgery · doi:10.1016/j.jtcvs.2012.04.006 · Cited by 22
Self-citation
Metadata
- Authors
- DEZFULIAN, C., RAAT, N., SHIVA, S., & GLADWIN, M.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- GLADWIN, M
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-07-15
- Volume
- 75
- Issue
- 2
- Pages
- 327-338
- ISSN
- 0008-6363 (ISSN-L)
- PMC
- PMC2002522
- OpenAlex
- W2128346933
- Cited by
- 198
- References
- 115
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 2 · 2021: 6 · 2020: 3 · 2019: 4 · 2018: 8 · 2017: 10 · 2016: 11 · 2015: 12 · 2014: 15 · 2013: 15 · 2012: 21
- FWCI
- 12.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cardiovascular Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99CL999999)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Keywords
- nitrite, nitric oxide, ischemia-reperfusion injury, cytoprotection, nitrite reduction, nitrate, hypoxia, heart, liver, brain, kidney
- MeSH terms
- Animals, Anions, Humans, Nitric Oxide, Nitrites, Signal Transduction, Reperfusion Injury, Cytoprotection, Models, Animal, Muscle Cells
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