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Identification of protein targets underlying dietary nitrate-induced protection against doxorubicin cardiotoxicity.
J Cell Mol Med 2011; 15(11):2512-24JC

Abstract

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.

Authors+Show Affiliations

VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298–0204, USA. lxi@vcu.edu

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21251210

Citation

Xi, Lei, et al. "Identification of Protein Targets Underlying Dietary Nitrate-induced Protection Against Doxorubicin Cardiotoxicity." Journal of Cellular and Molecular Medicine, vol. 15, no. 11, 2011, pp. 2512-24.
Xi L, Zhu SG, Hobbs DC, et al. Identification of protein targets underlying dietary nitrate-induced protection against doxorubicin cardiotoxicity. J Cell Mol Med. 2011;15(11):2512-24.
Xi, L., Zhu, S. G., Hobbs, D. C., & Kukreja, R. C. (2011). Identification of protein targets underlying dietary nitrate-induced protection against doxorubicin cardiotoxicity. Journal of Cellular and Molecular Medicine, 15(11), pp. 2512-24. doi:10.1111/j.1582-4934.2011.01257.x.
Xi L, et al. Identification of Protein Targets Underlying Dietary Nitrate-induced Protection Against Doxorubicin Cardiotoxicity. J Cell Mol Med. 2011;15(11):2512-24. PubMed PMID: 21251210.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of protein targets underlying dietary nitrate-induced protection against doxorubicin cardiotoxicity. AU - Xi,Lei, AU - Zhu,Shu-Guang, AU - Hobbs,Daniel C, AU - Kukreja,Rakesh C, PY - 2011/1/22/entrez PY - 2011/1/22/pubmed PY - 2012/4/11/medline SP - 2512 EP - 24 JF - Journal of cellular and molecular medicine JO - J. Cell. Mol. Med. VL - 15 IS - 11 N2 - 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. SN - 1582-4934 UR - https://www.unboundmedicine.com/medline/citation/21251210/Identification_of_protein_targets_underlying_dietary_nitrate_induced_protection_against_doxorubicin_cardiotoxicity_ L2 - https://doi.org/10.1111/j.1582-4934.2011.01257.x DB - PRIME DP - Unbound Medicine ER -