Dietary nitrate and nitrite modulate blood and organ nitrite and the cellular ischemic stress response
Open accessAbstract
Dietary nitrate, found in abundance in green vegetables, can be converted to the cytoprotective molecule nitrite by oral bacteria, suggesting that nitrate and nitrite may represent active cardioprotective constituents of the Mediterranean diet. We therefore tested the hypothesis that dietary nitrate and nitrite levels modulate tissue damage and ischemic gene expression in a mouse liver ischemia-reperfusion model. We found that stomach content, plasma, heart, and liver nitrite levels were significantly reduced after dietary nitrate and nitrite depletion and could be restored to normal levels with nitrite supplementation in water. Remarkably, we confirmed that basal nitrite levels significantly reduced liver injury after ischemia-reperfusion. Consistent with an effect of nitrite on the posttranslational modification of complex I of the mitochondrial electron transport chain, the severity of liver infarction was inversely proportional to complex I activity after nitrite repletion in the diet. The transcriptional response of dietary nitrite after ischemia was more robust than after normoxia, suggesting a hypoxic potentiation of nitrite-dependent transcriptional signaling. Our studies indicate that normal dietary nitrate and nitrite levels modulate ischemic stress responses and hypoxic gene expression programs, supporting the hypothesis that dietary nitrate and nitrite are cytoprotective components of the diet.
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Webb et al. showed conversion of nitrite to nitric oxide that was dependent on XOR.
“They could show conversion of nitrite to nitric oxide, which was dependent on XOR.”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [139]
The Introduction (page unavailable) describes xanthine oxidoreductase as one enzyme that activates nitrite to produce nitric oxide. The References list a Webb-led study on nitrite reduction during ischemia, but our copy does not say that Webb and colleagues showed the conversion was dependent on XOR. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn 2004, Webb et al. reported protective effects of nitrite in isolated perfused heart preparations subjected to I/R injury.
“In 2004, Webb et al. reported protective effects of nitrite in isolated perfused heart preparations subjected to I/R injury.139”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [139]
The Introduction reports that nitrite limits injury in animal models of heart ischemia-reperfusion, and reference 7 identifies a 2004 Webb et al. paper on protection against myocardial ischemia-reperfusion damage. Neither passage says the work used isolated perfused heart preparations; that specific detail is unsupported by our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAnimal models chronically fed a nitrate/nitrite-deficient diet exhibit diminished plasma and tissue nitrate/nitrite and increased ischemia-reperfusion injuries in heart and liver compared with normal-diet animals.
“animal models chronically fed a diet deficient in nitrate/nitrite exhibit significantly diminished plasma and tissue levels of nitrate/nitrite, resulting in increased ischemia-reperfusion injuries in heart and liver compared with the animal models fed a normal diet [29,30].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [30]
Vascular NO availability is expected to be impaired due to reduced NOS activity in ischemia and subsequent consumption by superoxide during reperfusion, resulting in severe ischemia/reperfusion injury.
“The availability of vascular NO would thus be expected to be impaired due to the reduced NOS activity in ischemia and subsequent consumption by superoxide during reperfusion [95], resulting in severe ischemia/reperfusion injury [30].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [30]
Nitrate-rich diets increase plasma and tissue levels of nitrite, but this cannot be accounted solely by nitrate reduction from oral bacteria.
“Recent and past data have demonstrated that nitrate-rich diets increase plasma and tissue levels of nitrite [9,10], but this cannot be accounted solely by nitrate reduction from oral bacteria and other mechanisms have been implicated and are under investigation [11].”
From Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions (2015) · cites this paper as [10]
Low concentrations of nitrite mediate cytoprotection in a variety of tissues in animal models including heart, liver, brain, kidney, hindlimb, and human forearm.
“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 [123]
Nitrite administration reduces skeletal muscle, renal, and liver injury after ischemia.
“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 [154]
In vivo administration of nitrite via direct infusion, dietary supplementation, or its two-electron oxidized precursor nitrate leads to a decrease in blood pressure in normal and hypertensive patients with a concomitant increase in markers of NO formation.
“in vivo administration of nitrite either via direct infusion [25, 37, 83], dietary supplementation [84-86] or in the form of its two-electron oxidized precursor nitrate [87-89] leads to a decrease in blood pressure in normal and hypertensive patients with a concomitant increase in markers of NO formation”
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 [86]
Nitrite-induced S-nitrosation of complex I of the electron transport chain decreases mitochondrial reactive species formation and subsequently confers protection against ischemia-reperfusion injury.
“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 [86]
Diet has the potential to contribute significantly to nitrite-dependent responses.
“several studies have shown that it has the potential to contribute significantly to nitrite-dependent responses [84, 86-89, 118-121]”
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 [86]
Diet is an important source of nitrite, largely via secondary reduction from nitrate.
“the diet is an important source of nitrite (largely via secondary reduction from nitrate)”
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 [86]
Nitrite anion is a reversible metabolite of NO that facilitates endogenous signaling responses differentially affecting gene expression.
“However, nitrite anion has emerged as a reversible metabolite of NO that facilitates endogenous signaling responses differentially affecting gene expression [3, 4], serves as a diagnostic marker of cardiovascular health, and acts as a potential therapeutic agent for several disease states.”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [4]
Nitrite therapy potently decreases mitochondrial respiration during ischemia, thereby preventing uncoupling of electron transport that increases reactive oxygen species formation leading to cytochrome c release and apoptosis activation.
“Subsequent work by the same group revealed that nitrite therapy potently decreases mitochondrial respiration during ischemia thereby preventing uncoupling of electron transport that increases reactive oxygen species formation leading to cytochrome c release and apoptosis activation [4, 39, 40].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [4]
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- Authors
- Raat, N. J. H., Noguchi, A. C., Liu, V. B., Raghavachari, N., Liu, D., Xu, X., Shiva, S., Munson, P. J., & Gladwin, M. T.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Gladwin, Mark T.
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 47
- Issue
- 5
- Pages
- 510-517
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC2744499
- OpenAlex
- W2046285486
- Cited by
- 97
- References
- 40
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 2 · 2018: 5 · 2017: 3 · 2016: 3 · 2015: 12 · 2014: 10 · 2013: 16 · 2012: 3
- FWCI
- 5.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (NIH0010039742)
- U.S. Public Health Service (NIH0010039742)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- dietary nitrate, dietary nitrite, nitrite supplementation, hepatic ischemia-reperfusion injury, hypoxia, mitochondrial complex I, cytoprotection, gut microbiota, Mediterranean diet
- MeSH terms
- Animals, Animal Structures, Diet, Gastric Mucosa, Heart, Ischemia, Liver, Mice, Inbred C57BL, Myocardium, Nitrates, Nitrites, Reperfusion Injury, Cytoprotection, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Mice
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