Identification of protein targets underlying dietary nitrate-induced protection against doxorubicin cardiotoxicity
Open accessAbstract
We recently demonstrated protective effect of chronic oral nitrate supplementation against cardiomyopathy caused by doxorubicin (DOX), a highly effective anticancer drug. The present study was designed to identify novel protein targets related to nitrate-induced cardioprotection. Adult male CF-1 mice received cardioprotective regimen of nitrate (1 g NaNO(3) per litre of drinking water) for 7 days before DOX injection (15 mg/kg, i.p.) and continued for 5 days after DOX treatment. Subsequently the heart samples were collected for proteomic analysis with two-dimensional differential in-gel electrophoresis with 3 CyDye labelling. Using 1.5 cut-off ratio, we identified 36 proteins that were up-regulated by DOX in which 32 were completely reversed by nitrate supplementation (89%). Among 19 proteins down-regulated by DOX, 9 were fully normalized by nitrate (47%). The protein spots were further identified with Matrix Assisted Laser Desorption/Ionization-Time-of-Flight (MALDI-TOF)/TOF tandem mass spectrometry. Three mitochondrial antioxidant enzymes were altered by DOX, i.e. up-regulation of manganese superoxide dismutase and peroxiredoxin 3 (Prx3), and down-regulation of Prx5, which were reversed by nitrate. These results were further confirmed by Western blots. Nitrate supplementation also significantly improved animal survival rate from 80% in DOX alone group to 93% in Nitrate + DOX group 5 days after the DOX treatment. In conclusion, the proteomic analysis has identified novel protein targets underlying nitrate-induced cardioprotection. Up-regulation of Prx5 by nitrate may explain the observed enhancement of cardiac antioxidant defence by nitrate supplementation.
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Nitrate normalizes mitochondrial-specific antioxidant proteins in a cardiotoxicity model in mice.
“nitrate normalizes mitochondrial-specific antioxidant proteins in a cardiotoxicity model in mice (196)”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [196]
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- Authors
- Xi, L., Zhu, S.-G., Hobbs, D. C., & Kukreja, R. C.
- Affiliations
- Virginia Commonwealth University (US)
- Corresponding author
- Xi, Lei
- Venue
- Journal of Cellular and Molecular Medicine
- Publisher
- Wiley
- Published
- 2011-10-24
- Volume
- 15
- Issue
- 11
- Pages
- 2512-2524
- ISSN
- 1582-1838 (ISSN-L)
- PMC
- PMC3110615
- OpenAlex
- W1983474087
- Cited by
- 27
- References
- 40
- Citations by year
- 2025: 2 · 2024: 2 · 2022: 1 · 2021: 2 · 2020: 2 · 2016: 3 · 2015: 4 · 2014: 4 · 2013: 3 · 2012: 3
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cellular and Molecular Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- U.S. Food and Drug Administration
- National Heart, Lung, and Blood Institute (R01HL051045, HL 51045, R01HL093685, R01HL079424, R37HL051045, HL-93685, HL-79424)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Chemotherapy-induced cardiotoxicity and mitigation
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- dietary nitrate, doxorubicin cardiotoxicity, cardioprotection, protein targets, mitochondrial antioxidant enzymes, peroxiredoxin 5, peroxiredoxin 3, manganese superoxide dismutase, cardiac proteome, nitrate supplementation, heart failure survival
- MeSH terms
- Animals, Antibiotics, Antineoplastic, Antioxidants, Cardiotonic Agents, Doxorubicin, Heart, Male, Cardiomyopathies, Nitrates, Nitric Oxide, Superoxide Dismutase, Survival, Oxidative Stress, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Myocytes, Cardiac, Proteomics, Mice, Peroxiredoxins, Cardiotoxins, Peroxiredoxin III
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