Dietary Nitrate Supplementation Protects Against Doxorubicin-Induced Cardiomyopathy by Improving Mitochondrial Function
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Objectives The aim of this study was to test the hypothesis that long-term dietary nitrate supplementation protects against doxorubicin-induced cardiomyopathy by improving ventricular function and reducing mitochondrial respiratory chain damage.Background Doxorubicin is a powerful anthracycline antibiotic used to treat divergent human neoplasms. Its clinical use is limited because of severe cardiotoxic side effects. Dietary nitrate and nitrite are essential nutrients for maintenance of steady-state tissue levels of nitric oxide and may play a therapeutic role in diseases associated with nitric oxide insufficiency or dysregulation. Dietary nitrate and nitrite supplementation alleviates myocardial injury caused by ischemia-reperfusion and cardiac arrest-resuscitation.Methods Adult male CF-1 mice were given a single dose of doxorubicin (15 mg/kg intraperitoneally), and left ventricular contractile function was assessed 5 days later using both echocardiography and pressure-volume Millar catheterization. A nitrate supplementation regimen (1 g/l sodium nitrate in drinking water) was started 7 days before doxorubicin injection and continued thereafter. Cardiomyocyte necrosis and apoptosis, tissue lipid peroxidation, and plasma nitrate and nitrite levels were assessed. In addition, mitochondrial complex I activity, oxidative phosphorylation capacity, and hydrogen peroxide generation were determined in parallel experiments.Results Doxorubicin caused impairment of ventricular contractility and cell death, which were significantly reduced by nitrate supplementation (p < 0.05). These cardioprotective effects were associated with a significant decrease in tissue lipid peroxidation. Nitrate supplementation significantly preserved mitochondrial complex I activity and oxidative phosphorylation and attenuated hydrogen peroxide generation after doxorubicin treatment.Conclusions Long-term oral intake of inorganic nitrate attenuates doxorubicin-induced ventricular dysfunction, cell death, oxidative stress, and mitochondrial respiratory chain damage. Nitrate could be a promising therapeutic agent against doxorubicin-induced cardiotoxicity.
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Nitrate supplementation offers cardioprotection against doxorubicin-induced cardiomyopathy and prevents oxidative stress and cardiovascular and renal injury in salt-induced hypertension.
“In addition, nitrate supplementation offered cardioprotection against doxorubicin-induced cardiomyopathy 37 and prevented oxidative stress and cardiovascular and renal injury in salt-induced hypertension.39”
From Dietary nitrate supplementation improves revascularization in chronic ischemia (2012) · cites this paper as [37]
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- Authors
- Zhu, S.-G., Kukreja, R. C., Das, A., Chen, Q., Lesnefsky, E. J., & Xi, L.
- Affiliations
- Virginia Commonwealth University (US)
- Corresponding author
- Kukreja, Rakesh C.
- Xi, Lei
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 57
- Issue
- 21
- Pages
- 2181-2189
- ISSN
- 0735-1097 (ISSN-L)
- PMC
- PMC4127335
- OpenAlex
- W2150992670
- Cited by
- 96
- References
- 62
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 7 · 2016: 7 · 2015: 10 · 2014: 9 · 2013: 8 · 2012: 10
- FWCI
- 6.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (HL51045, HL79424, HL93685, AG15885)
- American Heart Association (0530157N, 0765273U)
- Medical Research Service, U.S. Department of Veterans Affairs
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Chemotherapy-induced cardiotoxicity and mitigation
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- dietary nitrate, doxorubicin, anthracycline cardiotoxicity, cardiomyopathy, mitochondrial function, mitochondrial complex I, oxidative phosphorylation, lipid peroxidation, oxidative stress, ventricular contractility, cardiomyocyte apoptosis, hydrogen peroxide, nitric oxide
- MeSH terms
- Animals, Antibiotics, Antineoplastic, Doxorubicin, Electron Transport, Male, Mitochondria, Heart, Cardiomyopathies, Nitrates, Nitrites, Oxidative Phosphorylation, Oxidative Stress, Dietary Supplements, Mice
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