Nitrite Potently Inhibits Hypoxic and Inflammatory Pulmonary Arterial Hypertension and Smooth Muscle Proliferation via Xanthine Oxidoreductase–Dependent Nitric Oxide Generation
Abstract
Background—Pulmonary arterial hypertension is a progressive proliferative vasculopathy of the small pulmonary arteries that is characterized by a primary failure of the endothelial nitric oxide and prostacyclin vasodilator pathways, coupled with dysregulated cellular proliferation. We have recently discovered that the endogenous anion salt nitrite is converted to nitric oxide in the setting of physiological and pathological hypoxia. Considering the fact that nitric oxide exhibits vasoprotective properties, we examined the effects of nitrite on experimental pulmonary arterial hypertension. Methods and Results—We exposed mice and rats with hypoxia or monocrotaline-induced pulmonary arterial hypertension to low doses of nebulized nitrite (1.5 mg/min) 1 or 3 times a week. This dose minimally increased plasma and lung nitrite levels yet completely prevented or reversed pulmonary arterial hypertension and pathological right ventricular hypertrophy and failure. In vitro and in vivo studies revealed that nitrite in the lung was metabolized directly to nitric oxide in a process significantly enhanced under hypoxia and found to be dependent on the enzymatic action of xanthine oxidoreductase. Additionally, physiological levels of nitrite inhibited hypoxia-induced proliferation of cultured pulmonary artery smooth muscle cells via the nitric oxide–dependent induction of the cyclin-dependent kinase inhibitor p21 Waf1/Cip1. The therapeutic effect of nitrite on hypoxia-induced pulmonary hypertension was significantly reduced in the p21-knockout mouse; however, nitrite still reduced pressures and right ventricular pathological remodeling, indicating the existence of p21-independent effects as well. Conclusion—These studies reveal a potent effect of inhaled nitrite that limits pathological pulmonary arterial hypertrophy and cellular proliferation in the setting of experimental pulmonary arterial hypertension.
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The effects of low-dose nitrite in those models were independent of NOS and abolished by coadministration of the nitric oxide scavenger cPTIO, suggesting nitrite-derived nitric oxide as an active mediator.
“The effects were independent of NOS and abolished by coadministration of the nitric oxide scavenger cPTIO, suggesting nitrite-derived nitric oxide as an active mediator.”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [140]
The efficiency profile of nitrite therapy on liver and heart function was U-shaped, with a maximum protective effect reached at a dose of 48 nmol of nitrite.
“Furthermore, the efficiency profile of nitrite therapy on liver and heart function was U-shaped, with a maximum protective effect reached at a dose of 48 nmol of nitrite.”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [140]
Duranski et al. demonstrated potent cytoprotective effects of low-dose nitrite in vivo in mouse models of myocardial infarction and liver ischemia.
“Duranski et al. then demonstrated potent cytoprotective effects of low-dose nitrite in vivo in mouse models of myocardial infarction and liver ischemia.140”
From Nitrate-Nitrite-Nitric Oxide Pathway: Implications for Anesthesiology and Intensive Care (2010) · cites this paper as [140]
ADMA was recognized as an important marker for cardiovascular disease progression soon after its discovery in cells and tissue.
“Soon after its discovery in cells and tissue, ADMA was recognized as an important marker for cardiovascular disease progression (656, 829, 961, 1011, 1053, 1068).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [1068]
Nitrite is capable of inhibiting both hypoxia-induced and monocrotaline-induced PH in rats.
“and is capable of inhibiting both hypoxia-induced and monocrotaline-induced PH in rats[145].”
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 [145]
Inhaled nitrite inhibited hypoxia- and inflammation-induced pulmonary arterial hypertension in a murine model.
“In a slightly different context, inhaled nitrite was demonstrated to inhibit hypoxia and inflammation-induced pulmonary arterial hypertension in a murine model”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [130]
The effects of inhaled nitrite on pulmonary arterial hypertension were dependent on NO generation, which was greatly attenuated upon administration of allopurinol.
“and these effects were shown to be dependent on NO generation which was greatly attenuated upon administration of allopurinol [130].”
From Mechanisms of nitrite bioactivation (2014) · cites this paper as [130]
Some therapeutic effects of nitrite are sensitive to xanthine oxidoreductase inhibition.
“some therapeutic effects of nitrite are sensitive to xanthine oxidoreductase inhibition [73, 74]”
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 [74]
Nitrite supplementation has been shown to inhibit smooth muscle proliferation by induction of p21Waf1/Cip1.
“nitrite supplementation has been shown to inhibit smooth muscle proliferation by induction of p21Waf1/Cip1 [74]”
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 [74]
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References 50 · Cited by 192
- Authors
- Zuckerbraun, B. S., Shiva, S., Ifedigbo, E., Mathier, M. A., Mollen, K. P., Rao, J., Bauer, P. M., Choi, J. J. W., Curtis, E., Choi, A. M. K., & Gladwin, M. T.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- Circulation
- Published
- 2010-01-05
- Volume
- 121
- Issue
- 1
- Pages
- 98-109
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2151182465
- Cited by
- 192
- References
- 50
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 5 · 2022: 4 · 2021: 10 · 2020: 9 · 2019: 8 · 2018: 12 · 2017: 14 · 2016: 19 · 2015: 14 · 2014: 17 · 2013: 18 · 2012: 25
- FWCI
- 15.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL085134)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Genetics › Vascular Anomalies and Treatments
- Keywords
- nitrite, pulmonary arterial hypertension, xanthine oxidoreductase, nitric oxide, hypoxia, pulmonary artery smooth muscle cell proliferation, p21, right ventricular hypertrophy, monocrotaline, inflammation
- MeSH terms
- Administration, Inhalation, Animals, Hypoxia, Cell Division, Cells, Cultured, Chronic Disease, Disease Models, Animal, Hypertension, Pulmonary, Male, Mice, Inbred C57BL, Nitric Oxide, Pulmonary Artery, Sodium Nitrite, Xanthine Dehydrogenase, Monocrotaline, Rats, Sprague-Dawley, Mice, Knockout, Myocytes, Smooth Muscle, Cyclin-Dependent Kinase Inhibitor p21, Mice, Rats
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