Nitrite therapy improves left ventricular function during heart failure via restoration of nitric oxide-mediated cytoprotective signaling
Open accessAbstract
RATIONALE: Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is metabolized to NO during pathological states. We have previously demonstrated that sodium nitrite ameliorates acute myocardial ischemia/reperfusion injury. OBJECTIVE: No evidence exists as to whether increasing NO bioavailability via nitrite therapy attenuates heart failure severity after pressure-overload-induced hypertrophy. METHODS AND RESULTS: Serum from patients with heart failure exhibited significantly decreased nitrosothiol and cGMP levels. Transverse aortic constriction was performed in mice at 10 to 12 weeks. Sodium nitrite (50 mg/L) or saline vehicle was administered daily in the drinking water postoperative from day 1 for 9 weeks. Echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks after transverse aortic constriction to assess left ventricular dimensions and ejection fraction. We observed increased cardiac nitrite, nitrosothiol, and cGMP levels in mice treated with nitrite. Sodium nitrite preserved left ventricular ejection fraction and improved left ventricular dimensions at 9 weeks (P<0.001 versus vehicle). In addition, circulating and cardiac brain natriuretic peptide levels were attenuated in mice receiving nitrite (P<0.05 versus vehicle). Western blot analyses revealed upregulation of Akt-endothelial nitric oxide-nitric oxide-cGMP-GS3Kβ signaling early in the progression of hypertrophy and heart failure. CONCLUSIONS: These results support the emerging concept that nitrite therapy may be a viable clinical option for increasing NO levels and may have a practical clinical use in the treatment of heart failure.
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Functional resilience to debilitating diseases such as PH may be conferred by microbes via improved exercise capacity, oxygen utilization, and myocardial function.
“Functional resilience to debilitating diseases such as PH may also be conferred by microbes via improved exercise capacity, oxygen utilization, and myocardial function[126].”
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 [126]
Dietary nitrite improved cardiac fibrosis associated with pressure-overloaded left ventricular hypertrophy through NO-mediated cytoprotective signaling.
“They also showed that dietary nitrite improved the cardiac fibrosis associated with pressure-overloaded left ventricular hypertrophy through NO-mediated cytoprotective signaling [92].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [92]
Bhushan et al. reported that dietary nitrite supplementation in drinking water (50 mg/L sodium nitrite, for nine weeks) increased cardiac nitrite, nitrosothiol, and cGMP levels, which improved left ventricular function during heart failure in mice with hypertension produced by transverse aortic constriction.
“Bhushan et al., reported that dietary nitrite supplementation in drinking water (50 mg/L sodium nitrite, for nine weeks) increased the cardiac nitrite, nitrosothiol, and cGMP levels, which improved the left ventricular function during heart failure in mice with hypertension produced by transverse aortic constriction.”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [92]
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Self-citation
- Authors
- Bhushan, S., Kondo, K., Polhemus, D. J., Otsuka, H., Nicholson, C. K., Tao, Y.-X., Huang, H., Georgiopoulou, V. V., Murohara, T., Calvert, J. W., Butler, J., & Lefer, D. J.
- Affiliations
- Emory University (US)
- ORCID
- Venue
- Circulation Research
- Published
- 2014-04-11
- Volume
- 114
- Issue
- 8
- Pages
- 1281-1291
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC4943032
- OpenAlex
- W2112954543
- Cited by
- 69
- References
- 46
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 7 · 2022: 3 · 2021: 3 · 2020: 6 · 2019: 2 · 2018: 9 · 2017: 10 · 2016: 10 · 2015: 10 · 2014: 2
- FWCI
- 7.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL098481, R01HL093579, U24HL094373, P20HL113452, R01HL092141, R01HL116571, R01HL060849)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- nitrite therapy, sodium nitrite, heart failure, left ventricular function, nitric oxide bioavailability, S-nitrosothiols, cyclic GMP, pressure overload, cardiac hypertrophy, transverse aortic constriction, brain natriuretic peptide, Akt signaling, endothelial nitric oxide synthase
- MeSH terms
- Aged, Animals, Biological Availability, Disease Models, Animal, Female, Cyclic GMP, Heart Failure, Hemodynamics, Humans, Male, Mice, Inbred C57BL, Middle Aged, Nitric Oxide, Sodium Nitrite, Stroke Volume, Signal Transduction, Ventricular Dysfunction, Left, Cytoprotection, MAP Kinase Signaling System, Mice
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