The DOI matches its Crossref record; 70 of the 70 references it cites were found in a registry or an index.
Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver
Open accessAbstract
Nitrite represents a circulating and tissue storage form of NO whose bioactivation is mediated by the enzymatic action of xanthine oxidoreductase, nonenzymatic disproportionation, and reduction by deoxyhemoglobin, myoglobin, and tissue heme proteins. Because the rate of NO generation from nitrite is linearly dependent on reductions in oxygen and pH levels, we hypothesized that nitrite would be reduced to NO in ischemic tissue and exert NO-dependent protective effects. Solutions of sodium nitrite were administered in the setting of hepatic and cardiac ischemia-reperfusion (I/R) injury in mice. In hepatic I/R, nitrite exerted profound dose-dependent protective effects on cellular necrosis and apoptosis, with highly significant protective effects observed at near-physiological nitrite concentrations. In myocardial I/R injury, nitrite reduced cardiac infarct size by 67%. Consistent with hypoxia-dependent nitrite bioactivation, nitrite was reduced to NO, S-nitrosothiols, N-nitros-amines, and iron-nitrosylated heme proteins within 1-30 minutes of reperfusion. Nitrite-mediated protection of both the liver and the heart was dependent on NO generation and independent of eNOS and heme oxygenase-1 enzyme activities. These results suggest that nitrite is a biological storage reserve of NO subserving a critical function in tissue protection from ischemic injury. These studies reveal an unexpected and novel therapy for diseases such as myocardial infarction, organ preservation and transplantation, and shock states.
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In the citing paper
“Furthermore, the process was demonstrated to be dependent on xanthine oxidoreductase (XOR)”
From Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway (2013) · cites this paper as [160]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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 [186]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Early research indicated a therapeutic role for nitric oxide in cardioprotection in myocardial infarction models, 135 and L-arginine treatment before reperfusion was also organ-protective.133,136,137”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [135]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Pre-clinical studies with nitrate or nitrite also show the potential to protect against ischaemia-reperfusion injury and reduce arterial stiffness, inflammation and intimal thickness.”
From Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway (2013) · cites this paper as [160]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Chronic inhibition of XOR with allopurinol or 3 weeks of tungstenrich diet increased intimal hyperplasia.”
From Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway (2013) · cites this paper as [160]
Experimental — accuracy not yet measured
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Even the late introduction of nitrite was able to reverse intimal hyperplasia [160].”
From Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway (2013) · cites this paper as [160]
Experimental — accuracy not yet measuredIn the citing paper
“The nitrite (NO2−) anion protects from ischemia-reperfusion injury in vivo1–3,37 and is thought to act as an S-nitrosating agent in the ischemic myocardium2.”
From Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I (2013) · cites this paper as [1]
In the citing paper
“while nitrate supplementation prevents or limits ischemia-reperfusion injury and endothelial dysfunction in both animal[98,120–124] and human[97,125] models of ischemia-reperfusion.”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [121]
In the citing paper
“the nitrate/nitrite content of the fruits and vegetables could contribute to their cardiovascular health benefits in animals [29,33,78,79,80,81,82,83] and humans [31,84,85,86].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [79]
In the citing paper
“Physiologically relevant levels of nitrite have been shown to counter ischemic-reperfusion injury [8–10]”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [9]
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 [9]
In the citing paper
“pretreatment with this compound, delivered as a salt in the form of sodium nitrite, protects against ischemia/reperfusion (I/R) injury in the heart in preclinical models (7, 19, 20, 40, 46, 60, 79, 189).”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [46]
In the citing paper
“nitrite administration reduces skeletal muscle (188), renal (125, 179), and liver (46, 154, 169) injury after ischemia.”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [46]
In the citing paper
“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 [52]
In the citing paper
“Evidence for a role for NO is dependent largely on attenuation of responses by the NO-scavenger CPTIO [25, 26, 52, 100] and measurement of nitrite-dependent increases in cGMP levels[26, 101].”
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 [52]
In the citing paper
“Murine based studies of hepatic and myocardial IR injury have shown a ‘U’ shaped profile for nitrite effects; namely protection increases with increasing dose up to a point and then as the dose is increased further, protection is lost and can -if even higher doses are administered, exacerbate injury [52, 114].”
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 [52]
In the citing paper
“nitration reactions could also explain the loss of protection observed when higher doses of nitrite are administered in the context of IR injury [52, 114].”
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 [52]
In the citing paper
“the nitrite dose range encompassing protection versus loss of protection in these studies was greater than two or three orders of magnitude.”
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 [52]
In the citing paper
“experimental observations show that relatively low doses of nitrite are sufficient to induce dramatic protective effects in vivo.”
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 [52]
In the citing paper
“Typically doses of ~50 nmoles have been shown to be protective in models of ischemia reperfusion [52, 114] as well hemorrhagic shock in mice [122] for example.”
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 [52]
In the citing paper
“Duranski et al showed that nitrite therapy protects against ischemic tissue injury through a heme oxygenase-1 pathway which further implicated the generation of nitrite dependent NO during therapy.”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [156]
In the citing paper
“cPTIO treatment was shown by numerous groups to attenuate nitrite mediated protection against ischemia-reperfusion injury in vivo indicating that protective mechanisms likely involve NO dependent signaling pathways and molecular responses [47, 89, 156, 162].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [156]
In the citing paper
“This paper proved that near physiological doses of sodium nitrite (high nanomolar) were highly cytoprotective in both myocardial and hepatic ischemia-reperfusion extending previous work from Cosby et al demonstrating that near physiological levels of nitrite anion mediated hypoxic vasodilation responses [19].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [156]
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Citations
Cites
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“In addition, our data reveal a dynamic regulation of hepatic RxNOs, a pool of mercury-stable NO-modified proteins that include N-nitrosamines and iron-nitrosyl proteins (4, 50, 60), during I/R.”
Myocardial reperfusion: a double-edged sword?
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Cited by
Sorted by citations
Nitric Oxide and Peroxynitrite in Health and Disease
Pacher, P., Beckman, J. S., & Liaudet, L. (2007) · Physiological Reviews · doi:10.1152/physrev.00029.2006 · Cited by 6,390
The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics
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Self-citationReperfusion injury and reactive oxygen species: The evolution of a concept
Granger, D. N., & Kvietys, P. R. (2015) · Redox Biology · doi:10.1016/j.redox.2015.08.020 · Cited by 1,550
Mechanisms Underlying Acute Protection From Cardiac Ischemia-Reperfusion Injury
Murphy, E., & Steenbergen, C. (2008) · Physiological Reviews · doi:10.1152/physrev.00024.2007 · Cited by 1,504
“Nitrite has been shown to reduce ischemia-reperfusion injury (66).”
BackgroundMyocardial ischaemia–reperfusion injury and cardioprotection in perspective
Heusch, G. (2020) · Nature Reviews Cardiology · doi:10.1038/s41569-020-0403-y · Cited by 1,271
Metadata
- Authors
- 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., Gladwin, M. T., & Lefer, D. J.
- Affiliations
- Louisiana State University Health Sciences Center Shreveport (US)
- Medical College of Wisconsin (US)
- University of Alabama at Birmingham (US)
- Brigham and Women's Hospital (US)
- National Institutes of Health (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2005-04-14
- Volume
- 115
- Issue
- 5
- Pages
- 1232-1240
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1077170
- OpenAlex
- W2098453482
- Cited by
- 674
- References
- 70
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 9 · 2023: 7 · 2022: 21 · 2021: 22 · 2020: 20 · 2019: 18 · 2018: 23 · 2017: 40 · 2016: 31 · 2015: 45 · 2014: 42 · 2013: 42 · 2012: 59
- FWCI
- 28.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (2R01-HL60849, R01HL060849)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01-1 DK-43785, P01DK043785)
- 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, cardioprotection, hepatoprotection, sodium nitrite, S-nitrosothiols, nitrosamines, liver necrosis, apoptosis, organ preservation, myocardial infarction
- MeSH terms
- Animals, Heme Oxygenase (Decyclizing), Liver, Membrane Proteins, Mice, Inbred C57BL, Myocardium, Nitrites, Peritoneum, Reperfusion Injury, Nitric Oxide Synthase, Mice, Heme Oxygenase-1
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