Skip to main content

Peroxisome Proliferator-Activated Receptor-α Inhibition Protects Against Doxorubicin-Induced Cardiotoxicity in Mice


Doxorubicin is an effective chemotherapeutic drug against a considerable number of malignancies. However, its toxic effects on myocardium are confirmed as major limit of utilization. PPAR-α is highly expressed in the heart, and its activation leads to an increased cardiac fatty acid oxidation and cardiomyocyte necrosis. This study was performed to adjust the hypothesis that PPAR-α receptor inhibition protects against doxorubicin-induced cardiac dysfunction in mice. Male Balb/c mice were used in this study. Left atria were isolated, and their contractility was measured in response to electrical field stimulation in a standard organ bath. PPAR-α activity was measured using specific PPAR-α antibody in an ELISA-based system coated with double-strand DNA containing PPAR-α response element sequence. Moreover, cardiac MDA and TNF-α levels were measured by ELISA method. Following incubation with doxorubicin (35 µM), a significant reduction in atrial contractility was observed (P < 0.001). Pretreatment of animals with a selective PPAR-α antagonist, GW6471, significantly improved doxorubicin-induced atrial dysfunction (P < 0.001). Furthermore, pretreatment of the mice with a non-selective cannabinoid agonist, WIN55212-2, significantly decreased PPAR-α activity in cardiac tissue, subsequently leading to significant improvement in doxorubicin-induced atrial dysfunction (P < 0.001). Also, GW6471 and WIN significantly reduced cardiac MDA and TNF-α levels compared with animals receiving doxorubicin (P < 0.001). The study showed that inhibition of PPAR-α is associated with protection against doxorubicin-induced cardiotoxicity in mice, and cannabinoids can potentiate the protection by PPAR-α blockade. Moreover, PPAR-α may be considered as a target to prevent cardiotoxicity induced by doxorubicin in patients undergoing chemotherapy.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4



Peroxisome proliferator-activated receptor-α






Tumor necrosis factor-α




Enzyme-linked immunosorbent assay


  1. Ludke, A. R., Al-Shudiefat, A. A., Dhingra, S., Jassal, D. S., & Singal, P. K. (2009). A concise description of cardioprotective strategies in doxorubicin-induced cardiotoxicity. Canadian Journal of Physiology and Pharmacology, 87, 756–763.

    Article  PubMed  Google Scholar 

  2. Richard, C., Ghibu, S., Delemasure-Chalumeau, S., Guilland, J. C., Des Rosiers, C., Zeller, M., et al. (2011). Oxidative stress and myocardial gene alterations associated with doxorubicin-induced cardiotoxicity in rats persist for 2 months after treatment cessation. Journal of Pharmacology and Experimental Therapeutics, 339, 807–814.

    CAS  Article  PubMed  Google Scholar 

  3. Xi, L., Zhu, S. G., Das, A., Chen, Q., Durrant, D., Hobbs, D. C., et al. (2012). Dietary inorganic nitrate alleviates doxorubicin cardiotoxicity: Mechanisms and implications. Nitric Oxide, 26, 274–284.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Chatterjee, K., Zhang, J., Honbo, N., & Karlinerbc, J. S. (2010). Doxorubicin cardiomyopathy. Cardiology, 115, 155–162.

    CAS  Article  PubMed  Google Scholar 

  5. Simůnek, T., Stérba, M., Popelová, O., Adamcová, M., Hrdina, R., & Gersl, V. (2009). Anthracycline-induced cardiotoxicity: Overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacological Reports, 61, 154–171.

    Article  PubMed  Google Scholar 

  6. Hydock, D. S., Lien, C. Y., & Hayward, R. (2009). Anandamide preserves cardiac function and geometry in an acute doxorubicin cardiotoxicity rat model. Journal of Cardiovascular Pharmacology and Therapeutics, 14, 59–67.

    CAS  Article  PubMed  Google Scholar 

  7. Seely, K. A., Prather, P. L., James, L. P., & Moran, J. H. (2011). Marijuana-based drugs: Innovative therapeutics or designer drugs of abuse? Molecular Interventions, 11(1), 36–51.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. González, C., Herradón, E., Abalo, R., Vera, G., Pérez-Nievas, B. G., Leza, J. C., et al. (2011). Cannabinoid/agonist WIN 55,212-2 reduces cardiac ischaemia–reperfusion injury in Zucker diabetic fatty rats: Role of CB2 receptors and iNOS/eNOS. Diabetes/Metabolism Research and Reviews, 27, 331–340.

    Article  PubMed  Google Scholar 

  9. Hajrasouliha, A. R., Tavakoli, S., Ghasemi, M., Jabehdar-Maralani, P., Sadeghipour, H., Ebrahimi, F., et al. (2008). Endogenous cannabinoids contribute to remote ischemic preconditioning via cannabinoid CB2 receptors in the rat heart. European Journal of Pharmacology, 28, 246–252.

    Article  Google Scholar 

  10. Hiley, C. R., & Ford, W. R. (2004). Cannabinoid pharmacology in the cardiovascular system: Potential protective mechanisms through lipid signaling. Biological Reviews, 79, 187–205.

    Article  PubMed  Google Scholar 

  11. De Petrocellis, L., & Di Marzo, V. (2009). Role of endocannabinoids and endovanilloids in Ca2+ signalling. Cell calcium, 45(6), 611–624.

    Article  PubMed  Google Scholar 

  12. Sun, Y., & Bennett, A. (2007). Cannabinoids: A new group of agonists of PPARs. PPAR Research. doi:10.1155/2007/23513.

    PubMed  PubMed Central  Google Scholar 

  13. Ravingerova, T., Adameova, A., Carnicka, S., Nemcekova, M., Kelly, T., Matejikova, J., et al. (2001). The role of PPAR in myocardial response to ischemia in normal and diseased heart. General Physiology and Biophysics, 30, 329–341.

    Article  Google Scholar 

  14. Azhar, S. (2010). Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease. Future Cardiology, 6, 657–691.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Oyekan, A. (2011). PPARs and their effects on the cardiovascular system. Clinical and Experimental Hypertension, 33, 287–293.

    CAS  Article  PubMed  Google Scholar 

  16. Pruimboom-Brees, I., Haghpassand, M., Royer, L., Brees, D., Aldinger, C., Reagan, W., et al. (2006). A critical role for peroxisomal proliferator-activated receptor-alpha nuclear receptors in the development of cardiomyocyte degeneration and necrosis. The American Journal of Pathology, 169, 750–760.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Feridooni, T., Hotchkiss, A., Remley-Carr, S., Saga, Y., & Pasumarthi, K. B. (2011). Cardiomyocyte specific ablation of p53 is not sufficient to block doxorubicin induced cardiac fibrosis and associated cytoskeletal changes. PLoS One, 6, e22801.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Di Filippo, C., Rossi, F., Rossi, S., & D’Amico, M. (2004). Cannabinoid CB2 receptor activation reduces mouse myocardial ischemia-reperfusion injury: Involvement of cytokine/chemokines and PMN. Journal of Leukocyte Biology, 75, 453–459.

    Article  PubMed  Google Scholar 

  19. de Jong, J., Schoofs, P. R., Onderwater, R. C., van der Vijgh, W. J., Pinedo, H. M., & Bast, A. (1990). Isolated mouse atrium as a model to study anthracycline cardiotoxicity: The role of the beta-adrenoceptor system and reactive oxygen species. Research Communications in Chemical Pathology and Pharmacology, 68, 275–289.

    PubMed  Google Scholar 

  20. Costa, B., Comelli, F., Bettoni, I., Colleoni, M., & Giagnoni, G. (2008). The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: Involvement of CB(1), TRPV1 and PPARγ receptors and neurotrophic factors. Pain, 139, 541–550.

    CAS  Article  PubMed  Google Scholar 

  21. Hajiasgharzadeh, K., Mirnajafi-Zadeh, J., & Mani, A. R. (2001). Interleukin-6 impairs chronotropic responsiveness to cholinergic stimulation and decreases heart rate variability in mice. European Journal of Pharmacology, 673, 70–77.

    Article  Google Scholar 

  22. Haddadian, Z., Eftekhari, G., Mazloom, R., Jazaeri, F., Dehpour, A. R., & Mani, A. R. (2013). Effect of endotoxin on heart rate dynamics in rats with cirrhosis. Autonomic Neuroscience, 177, 104–113.

    CAS  Article  PubMed  Google Scholar 

  23. Rahimian, R., Fakhfouri, G., Daneshmand, A., Mohammadi, H., Bahremand, A., Rasouli, M. R., et al. (2010). Adenosine A2A receptors and uric acid mediate protective effects of inosine against TNBS-induced colitis in rats. European Journal of Pharmacology, 649(1–3), 376–381.

    CAS  Article  PubMed  Google Scholar 

  24. Sly, L. M., Rauh, M. J., Kalesnikoff, J., Song, C. H., & Krystal, G. (2004). LPS-induced upregulation of SHIP is essential for endotoxin tolerance. Immunity, 21, 227–239.

    CAS  Article  PubMed  Google Scholar 

  25. Mitra, M. S., Donthamsetty, S., White, B., Latendresse, J. R., & Mehendale, H. M. (2007). Mechanism of protection of moderately diet restricted rats against doxorubicin-induced acute cardiotoxicity. Toxicology and Applied Pharmacology, 225, 90–101.

    CAS  Article  PubMed  Google Scholar 

  26. Mitra, M. S., Donthamsetty, S., White, B., & Mehendale, H. M. (2008). High fat diet-fed obese rats are highly sensitive to doxorubicin-induced cardiotoxicity. Toxicology and Applied Pharmacology, 231, 413–422.

    CAS  Article  PubMed  Google Scholar 

  27. van Norren, K., van Helvoort, A., Argilés, J. M., van Tuijl, S., Arts, K., Gorselink, M., et al. (2009). Direct effects of doxorubicin on skeletal muscle contribute to fatigue. British Journal of Cancer, 100, 311–314.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Gaskari, S. A., Liu, H., Moezi, L., Li, Y., Baik, S. K., & Lee, S. S. (2005). Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct–ligated rats. British Journal of Pharmacology, 146, 315–323.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Guo, J., Guo, Q., Fang, H., Lei, L., Zhang, T., Zhao, J., & Peng, S. (2014). Cardioprotection against doxorubicin by metallothionein Is associated with preservation of mitochondrial biogenesis involving PGC-1α pathway. European Journal of Pharmacology, 737, 117–124.

    CAS  Article  PubMed  Google Scholar 

  30. Ahmed, L. A., & El-Maraghy, S. A. (2013). Nicorandil ameliorates mitochondrial dysfunction in doxorubicin-induced heart failure in rats: Possible mechanism of cardioprotection. Biochemical Pharmacology, 86, 1301–1310.

    CAS  Article  PubMed  Google Scholar 

  31. Yao, H., Shang, Z., Wang, P., Li, S., Zhang, Q., Tian, H., et al. (2015). Protection of luteolin-7-O-glucoside against doxorubicin-induced injury through PTEN/Akt and ERK pathway in H9c2 Cells. Cardiovascular Toxicology. doi:10.1007/s12012-015-9317-z.

    Google Scholar 

  32. Miyazaki, M., Nakagawa, I., Koga, S., Kasahara, Y., & Patricelli, M. P. (2010). Proteomics analysis of cardiac muscle from rats with peroxisomal proliferator-activated receptor alpha (PPAR-alpha) stimulation. Journal of Toxicological Sciences, 35, 31–35.

    Article  Google Scholar 

Download references


This study was supported by grants from Dean of Research, Tehran University of Medical Sciences. The authors would like to thank Miss Maryam Rahimi Balai and Dr Alireza Mani for cooperation during conduct of the study.

Conflict of interest

Authors declare no conflict of interest.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Ahmad Reza Dehpour.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rahmatollahi, M., Baram, S.M., Rahimian, R. et al. Peroxisome Proliferator-Activated Receptor-α Inhibition Protects Against Doxorubicin-Induced Cardiotoxicity in Mice. Cardiovasc Toxicol 16, 244–250 (2016).

Download citation

  • Published:

  • Issue Date:

  • DOI:


  • Peroxisome proliferator-activated receptor-α
  • Cannabinoids
  • Doxorubicin
  • Cardiotoxicity