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Molecular Medicine

, Volume 21, Issue 1, pp 38–45 | Cite as

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis

  • Enkui Hao
  • Partha Mukhopadhyay
  • Zongxian Cao
  • Katalin Erdélyi
  • Eileen Holovac
  • Lucas Liaudet
  • Wen-Shin Lee
  • György Haskó
  • Raphael Mechoulam
  • Pál Pacher
Research Article

Abstract

Doxorubicin (DOX) is a widely used, potent chemotherapeutic agent; however, its clinical application is limited because of its dose-dependent cardiotoxicity. DOX’s cardiotoxicity involves increased oxidative/nitrative stress, impaired mitochondrial function in cardiomyocytes/endothelial cells and cell death. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, with antioxidant, antiinflammatory and recently discovered antitumor properties. We aimed to explore the effects of CBD in a well-established mouse model of DOX-induced cardiomyopathy. DOX-induced cardiomyopathy was characterized by increased myocardial injury (elevated serum creatine kinase and lactate dehydrogenase levels), myocardial oxidative and nitrative stress (decreased total glutathione content and glutathione peroxidase 1 activity, increased lipid peroxidation, 3-nitrotyrosine formation and expression of inducible nitric oxide synthase mRNA), myocardial cell death (apoptotic and poly(ADP)-ribose polymerase 1 (PARP)-dependent) and cardiac dysfunction (decline in ejection fraction and left ventricular fractional shortening). DOX also impaired myocardial mitochondrial biogenesis (decreased mitochondrial copy number, mRNA expression of peroxisome proliferator-activated receptor γ coactivator 1-alpha, peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha), reduced mitochondrial function (attenuated complex I and II activities) and decreased myocardial expression of uncoupling protein 2 and 3 and medium-chain acyl-CoA dehydrogenase mRNA. Treatment with CBD markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. CBD also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that CBD may represent a novel cardioprotective strategy against DOX-induced cardiotoxicity, and the above-described effects on mitochondrial function and biogenesis may contribute to its beneficial properties described in numerous other models of tissue injury.

Notes

Acknowledgments

This study was supported by the Intramural Research Program of National Institutes of Health/NIAAA. P Pacher is grateful to George Kunos, Scientific Director of NIAAA, for continuous support, and dedicates this study to collaborator and friend, Itai Bab. The study also was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism (to P Pacher).

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Authors and Affiliations

  • Enkui Hao
    • 1
    • 2
  • Partha Mukhopadhyay
    • 1
  • Zongxian Cao
    • 1
  • Katalin Erdélyi
    • 1
  • Eileen Holovac
    • 1
  • Lucas Liaudet
    • 3
  • Wen-Shin Lee
    • 1
    • 4
  • György Haskó
    • 5
  • Raphael Mechoulam
    • 6
  • Pál Pacher
    • 1
    • 7
  1. 1.Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthBethesdaUSA
  2. 2.Department of Cardiology, Shandong Provincial Qianfoshan HospitalShandong UniversityJinanChina
  3. 3.Department of Intensive Care MedicineBH 08-621 University Hospital Medical CenterLausanneSwitzerland
  4. 4.Division of General Medicine, Department of Medicine, Taipei Veterans General HospitalNational Yang-Ming University School of MedicineTaipeiTaiwan
  5. 5.Departments of SurgeryRutgers New Jersey Medical SchoolNewarkUSA
  6. 6.Department for Medicinal Chemistry and Natural Products, Faculty of MedicineHebrew University of JerusalemJerusalemIsrael
  7. 7.Section on Oxidative Stress Tissue Injury, Laboratory of Physiological StudiesNational Institutes of Health/NIAAABethesdaUSA

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