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Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging: Sodium nitrite and vascular dysfunction with aging
Open accessAbstract
We tested the hypothesis that short-term nitrite therapy reverses vascular endothelial dysfunction and large elastic artery stiffening with aging, and reduces arterial oxidative stress and inflammation. Nitrite concentrations were lower (P < 0.05) in arteries, heart, and plasma of old (26-28 month) male C57BL6 control mice, and 3 weeks of sodium nitrite (50 mg L(-1) in drinking water) restored nitrite levels to or above young (4-6 month) controls. Isolated carotid arteries of old control mice had lower acetylcholine (ACh)-induced endothelium-dependent dilation (EDD) (71.7 ± 6.1% vs. 93.0 ± 2.0%) mediated by reduced nitric oxide (NO) bioavailability (P < 0.05 vs. young), and sodium nitrite restored EDD (95.5 ± 1.6%) by increasing NO bioavailability. 4-Hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL), a superoxide dismutase (SOD) mimetic, apocynin, a nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) inhibitor, and sepiapterin (exogenous tetrahydrobiopterin) each restored EDD to ACh in old control, but had no effect in old nitrite-supplemented mice. Old control mice had increased aortic pulse wave velocity (478 ± 16 vs. 332 ± 12 AU, P < 0.05 vs. young), which nitrite supplementation lowered (384 ± 27 AU). Nitrotyrosine, superoxide production, and expression of NADPH oxidase were ∼100-300% greater and SOD activity was ∼50% lower in old control mice (all P < 0.05 vs. young), but were ameliorated by sodium nitrite treatment. Inflammatory cytokines were markedly increased in old control mice (P < 0.05), but reduced to levels of young controls with nitrite supplementation. Short-term nitrite therapy reverses age-associated vascular endothelial dysfunction, large elastic artery stiffness, oxidative stress, and inflammation. Sodium nitrite may be a novel therapy for treating arterial aging in humans.
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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 [150]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Thus, Sindler et al. found that nitrite reduced the elevated pulse wave velocity and levels of inflammatory cytokines IL-1b, IL6, INFg and TNFa [150].”
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 [150]
The cited source says what the claim attributes to it.
In the citing paper
“Sindler et al. also detected depleted concentrations in the arteries and heart, which were restored to youthful levels (4-6 month controls) by 3 weeks' supplementation with sodium nitrite (50 mg l -1 in the drinking water) [150].”
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 [150]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“While the efficacy of dietary NO 3 -to reduce systemic blood pressure in older age has been extensively studied (reviewed in 140; see also 139, 142), relatively few studies have assessed the effects of NO 3 -supplementation on exercise capacity in healthy older individuals.”
From Dietary Nitrate and Physical Performance (2018) · cites this paper as [142]
Experimental — accuracy not yet measuredIn the citing paper
“Oral supplementation with either nitrite or nitrate increases circulating nitrite levels and prevents and reverses endothelial dysfunction in a dose-dependent manner both in mice[68,69] and in healthy[70,71,97,111,112], hypertensive[113], and obese individuals[114], or in those with hypercholesterolemia[115] and peripheral arterial disease[116].”
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 [69]
In the citing paper
“ameliorates endothelial dysfunction, as indicated by normalization of NO-mediated endothelium-dependent dilation.”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“In old mice, short-term oral sodium nitrite supplementation reduces aortic pulse wave velocity, the gold-standard measure of large elastic artery stiffness”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“These improvements in age-related vascular dysfunction with nitrite are mediated by reductions in oxidative stress and inflammation”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“vascular endothelial function as assessed by carotid artery EDD in response to acetylcholine, was impaired in old compared with young control animals (Fig. 4, top).”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“Sodium nitrite treatment restored EDD in old mice by increasing NO-dependent dilation (Fig. 4, bottom).”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“the staining intensity for nitrotyrosine, a cellular marker of oxidant modification of proteins, was markedly greater in aorta of old compared with young control mice (53, 171) (Fig. 5A).”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“Nitrite concentrations in the plasma and large elastic arteries (aorta and carotid arteries) were lower in older animals, but sodium nitrite supplementation increased nitrite concentrations in the old mice up to or above those of young control animals (Fig. 2) (171).”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“sodium nitrite had no effect on arterial function in the young mice in this study (171)”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“aortic PWV was markedly higher (i.e., the aorta was stiffer) in old compared with young control mice (Fig. 3A).”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“Sodium nitrite treatment normalized aortic nitrotyrosine staining in old mice, indicating amelioration of age-associated arterial oxidative stress.”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“Sodium nitrite treatment reduced aortic PWV in old mice to well below old controls and not significantly different from that in young animals.”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“Superoxide production was much greater in aorta from old compared with young control mice”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“Inhibition of NO using the NO synthase inhibitor l-NAME, markedly reduced EDD in young animals while having less effect in old mice, indicating that the impaired EDD in old animals was mediated by reduced NO bioavailability.”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“Nitrite did not affect endothelium-independent dilation to sodium nitroprusside (171), indicating that the improvements in EDD were not induced by increased vascular smooth muscle sensitivity to NO.”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“expression of the proinflammatory cytokines interleukin (IL)-1β, IL-6, interferon-γ, and tumor necrosis factor-α (TNF-α) were shown to be greater in aorta of old mice than young control mice (171)”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“although it had no effect on EDD in old mice treated with sodium nitrite (171)”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“The activity of the major antioxidant enzyme SOD was found to be ∼50% lower in aorta of old compared with young control mice”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“Protein expression of NADPH oxidase was threefold greater in aorta of old mice compared with those of young control mice”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“Inhibition of NADPH oxidase with apocynin had no effect on EDD in arteries of old animals treated with sodium nitrite”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“short-term treatment with sodium nitrite completely normalized superoxide formation in old animals (53, 171)”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“Sepiapterin restored acetylcholine-induced EDD selectively in carotid arteries of old control mice”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“TEMPOL had no effect on EDD in old mice treated with sodium nitrite”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“but restored EDD in old control mice (171)”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“short-term treatment with sodium nitrite restored SOD activity in aorta of old mice to levels observed in young controls”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“but completely restored EDD in old control animals”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“but this was normalized after sodium nitrite treatment”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
In the citing paper
“Most importantly, nitrite supplementation completely reversed this age-associated arterial inflammation (171).”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [171]
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Metadata
- Authors
- Sindler, A. L., Fleenor, B. S., Calvert, J. W., Marshall, K. D., Zigler, M. L., Lefer, D. J., & Seals, D. R.
- Affiliations
- University of Colorado Boulder (US)
- Emory University (US)
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2011-03-31
- Volume
- 10
- Issue
- 3
- Pages
- 429-437
- ISSN
- 1474-9718 (ISSN-L)
- PMC
- PMC3094511
- OpenAlex
- W1559904992
- Cited by
- 218
- References
- 56
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 11 · 2023: 8 · 2022: 12 · 2021: 17 · 2020: 16 · 2019: 15 · 2018: 14 · 2017: 17 · 2016: 19 · 2015: 23 · 2014: 22 · 2013: 11 · 2012: 17
- FWCI
- 12.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG-000279, R37AG013038, R01AG013038, AG-013038, T32AG000279)
- National Heart, Lung, and Blood Institute (R01HL098481, HL007822, R01HL093579, T32HL007822, HL092141, R01HL092141, HL093579)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- nitrite supplementation, sodium nitrite, endothelial dysfunction, arterial stiffness, aging, nitric oxide bioavailability, oxidative stress, inflammation, NADPH oxidase, superoxide, tempol, apocynin, sepiapterin, pulse wave velocity, carotid artery, nitrotyrosine, inflammatory cytokines, arterial aging
- MeSH terms
- Acetophenones, Acetylcholine, Administration, Oral, Aging, Animals, Biopterins, Carotid Arteries, Cyclic N-Oxides, Elasticity, Endothelium, Vascular, Humans, Male, Myography, Nitric Oxide, Sodium Nitrite, Spin Labels, Superoxide Dismutase, Vasodilation, Vasodilator Agents, Cytokines, Oxidative Stress, NADPH Oxidases, Mice
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