Heparin attenuates doxorubicin-induced cardiotoxicity in the rat model

Research Article  
American Journal of BioMedicine Volume 3, Issue 11, pages 739-753
Received: June 30, 2015; accepted: September 30, 2015; published: November 27, 2015

 Yoji Nanba, Noriko Watanabe, Henrik Suzukia mail of corresponding author


Doxorubicin (Dox) is a widely used chemotherapy drug, but its application is associated with cardiotoxicity. It was reported that doxorubicin-induced cardiotoxicity is mediated through oxidative stress coupled with impaired NO bioavailability and NF-κB activation. We investigated the effect of sequence administration of Doxorubicin on the severity of cardiotoxicity. Sprague Dawley rats were divided into three groups (n = 8) and followed for a total of 12 weeks: a) control-PBS-treated, b) Doxorubicin treated, and c) Doxorubicin + Heparin treated. Doxorubicin was administered via intraperitoneal injection 3.0 mg/kg at weekly intervals from week 2 through week 7. Heparin was administered via intraperitoneal injection. Cardiac function was assessed by echocardiography. At the end of the experiment, the rats were killed. Cardiac enzyme indexes were measured in serum. Heart tissues were processed for determination of NF-κB protein expression, glutathione (GSH), lipid peroxide (TBARS) levels and superoxide production, troponin-T (TnT) in effluate from the isolated hearts, and MCP-1 in both myocarial tissue and serum. Dox-treated mice exhibited severe cardiac dysfunction, and the mortality was higher than that in PBS-treated mice. In Dox-treated mice, the NF-κB protein expression was higher and the fibrotic areas were larger than in PBS-treated mice. The cardiotoxic effects of Dox were ameliorated by treatment with heparin. Our concluded that  heparin protects heart from Dox-induced cardiotoxicity by reduced NF-κB protein expression and inflammatory mediators.

Keywords: Doxorubicin; Heparin; Cardiotoxicity; NF-κB

Copyright © 2015 by The American Society for BioMedicine and BM-Publisher, Inc.



1. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 2004;56(2):185–229. [PubMed]

2. Ferreira AL, Matsubara LS, Matsubara BB. Anthracycline-induced cardiotoxicity. Cardiovasc Hematol Agents Med Chem 2008;6(4):278–281. [PubMed]

3. Garlid AO, Jaburek M, Jacobs JP, Garlid KD. Mitochondrial reactive oxygen species: which ROS signals cardioprotection? Am J Physiol Heart Circ Physiol 2013;305(7):H960–H968. [PubMed]

4. Sacco G, Bigioni M, Evangelista S, Goso C, Manzini S, Maggi CA. Cardioprotective effects of zofenopril, a new angiotensin-converting enzyme inhibitor, on doxorubicin-induced cardiotoxicity in the rat. Eur J Pharmacol 2001;414(1):71–78. [PubMed]

5. Lipshultz SE, Alvarez JA, Scully RE. Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart 2008;94(4):525–533. [PubMed]

6. Konorev EA, Kennedy MC, Kalyanaraman B. Cell-permeable superoxide dismutase and glutathione peroxidase mimetics afford superior protection against doxorubicin-induced cardiotoxicity: the role of reactive oxygen and nitrogen intermediates. Arch Biochem Biophys 1999;368(2):421–428. [PubMed]

7. Boucek RJ, Jr, Steele A, Miracle A, Atkinson J. Effects of angiotensin-converting enzyme inhibitor on delayed-onset doxorubicin-induced cardiotoxicity. Cardiovasc Toxicol 2003;3(4):319–329. [PubMed]

8. arrere-Lemaire S, Combes N, et al. Morphine mimics the antiapoptotic effect of preconditioning via an Ins(1,4,5)P3 signaling pathway in rat ventricular myocytes. Am J Physiol Heart Circ Physiol 2005;288(1):H83–H88. [PubMed]

9. Richard C, Lauzier B, Delemasure S, et al. Effects of angiotensin-1 converting enzyme inhibition on oxidative stress and bradykinin receptor expression during doxorubicin-induced cardiomyopathy in rats. J Cardiovasc Pharmacol 2008;52(3):278–285. [PubMed]

10. Zhu W, Soonpaa MH, Chen H, et al. Acute doxorubicin cardiotoxicity is associated with p53-induced inhibition of the mammalian target of rapamycin pathway. Circulation 2009;119(1):99–106. [PubMed]

11. Doughan AK, Harrison DG, Dikalov SI. Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res 2008;102(4):488–496. [PubMed]

12. Davidson SM, Duchen MR. Endothelial mitochondria: contributing to vascular function and disease. Circ Res 2007;100(8):1128–1141. [PubMed]

13. Wallace KB. Doxorubicin-induced cardiac mitochondrionopathy. Pharmacol Toxicol 2003;93(3):105–115. [PubMed]

14. Solem LE, Henry TR, Wallace KB. Disruption of mitochondrial calcium homeostasis following chronic doxorubicin administration. Toxicol Appl Pharmacol 1994;129(2):214–222. [PubMed]

15. Ascensao A, Magalhaes J, Soares JM, et al. Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces the development of cardiac apoptosis. Am J Physiol Heart Circ Physiol 2005;289(2):H722–731. [PubMed]

16. Yamanaka S, Tatsumi T, Shiraishi J, et al. Amlodipine inhibits doxorubicin-induced apoptosis in neonatal rat cardiac myocytes. J Am Coll Cardiol 2003;41:870-878. [PubMed]

17. Kontny NE, Würthwein G, Joachim B, et al. Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years. Cancer Chemother Pharmacol 2013;71:749-763. [PubMed]

18. YBartelink IH1, Boelens JJ, Bredius RG. Body weight-dependent pharmacokinetics of busulfan in paediatric haematopoietic stem cell transplantation patients: towards individualized dosing. Clin Pharmacokinet 2012;51(5):331-45. [PubMed]

19. Maejima Y, Kyoi S, Zhai P, et al. Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2. Nat Med 2013;19:1478-1488. [PubMed]

20. Childs AC1, Phaneuf SL, Dirks AJ, Phillips T, Leeuwenburgh C. Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio. Cancer Res 2002;62(16):4592-8. [PubMed]

21. Naik SR, Thakare VN, Patil SR. Protective effect of curcumin on experimentally induced inflammation, hepatotoxicity and cardiotoxicity in rats: evidence of its antioxidant property. Exp Toxicol Pathol 2011;63:419-431. [PubMed]

22. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 2004;56:85-229. [PubMed]

23. Akao M, O'Rourke B, Teshima Y, Seharaseyon J, Marban E. Mechanistically distinct steps in the mitochondrial death pathway triggered by oxidative stress in cardiac myocytes. Circ Res 2003;92:186-194. [PubMed]

24. Yousif NG, Al-Amran FG. Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice. BMC Cardiovasc Disord 2011;11:62. [PubMed]

25. Menna P1, Paz OG, Chello M, Covino E, Salvatorelli E, Minotti G. Anthracycline cardiotoxicity. Expert Opin Drug Saf 2012;11 Suppl 1:S21-36.

26. Batist G. Cardiac safety of liposomal anthracyclines. Cardiovasc Toxicol 2007;7:72–74. [PubMed]

27. Ganame J, Claus P, Uyttebroeck A, et al. Myocardial dysfunction late after low-dose anthracycline treatment in asymptomatic pediatric patients. J Am Soc Echocardiogr 2007;20:1351–1358. [PubMed]

28. Silber JH, Cnaan A, Clark BJ, et al. Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines. J Clin Oncol 2004;22:820–828. [PubMed]

29. Jones LW, Haykowsky MJ, Swartz JJ, et al. Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol 2007;50:1435–1441. [PubMed]

30. Hequet O, Le QH, Moullet I, et al. Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults. J Clin Onco 2004;22:1864–1871. [PubMed]

31. Minotti G, Sarvazyan N, editors. Cardiovasc Toxicol. 2007. Anthracycline cardiotoxicity: Molecular mechanisms and clinical correlates; pp. 7L53–7L167.

32. Pinder MC, Zhigang D, Goodwin JS, et al. Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol 2007;25:3808–3815. [PubMed]

33. Lebrecht D, Walker UA. Role of mtDNA lesions in anthracycline cardiotoxicity. Cardiovasc Toxicol 2007;7:108–113. [PubMed]

34. Kalay N, Basar E, Ozdogru I, et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2006;48:2258–2262. [PubMed]

35. Lipshultz SE, Cohen H, Colan SD, et al. The relevance of information generated by in vitro experimental models to clinical doxorubicin cardiotoxicity. Leuk Lymphoma 2006;47:1454–1458. [PubMed]

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