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, G. Haskó, Raphael Mechoulam, Pál Pacher

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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.

Original languageEnglish
Pages (from-to)38-45
Number of pages8
JournalMolecular Medicine
Volume21
DOIs
Publication statusPublished - Jan 6 2015

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Cannabidiol
Organelle Biogenesis
Cardiomyopathies
Doxorubicin
Oxidative Stress
Cell Death
Messenger RNA
Acyl-CoA Dehydrogenase
PPAR alpha
Peroxisome Proliferator-Activated Receptors
Ribose
Wounds and Injuries
Nitric Oxide Synthase Type II
Cannabis
Creatine Kinase
L-Lactate Dehydrogenase
Cardiac Myocytes
Stroke Volume
Lipid Peroxidation
Glutathione

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Cannabidiol protects against doxorubicin-induced cardiomyopathy by modulating mitochondrial function and biogenesis. / Hao, Enkui; Mukhopadhyay, Partha; Cao, Zongxian; Erdélyi, Katalin; Holovac, Eileen; Liaudet, Lucas; Lee, Wen Shin; Haskó, G.; Mechoulam, Raphael; Pacher, Pál.

In: Molecular Medicine, Vol. 21, 06.01.2015, p. 38-45.

Research output: Contribution to journalArticle

Hao, E, Mukhopadhyay, P, Cao, Z, Erdélyi, K, Holovac, E, Liaudet, L, Lee, WS, Haskó, G, Mechoulam, R & Pacher, P 2015, 'Cannabidiol protects against doxorubicin-induced cardiomyopathy by modulating mitochondrial function and biogenesis', Molecular Medicine, vol. 21, pp. 38-45. https://doi.org/10.2119/molmed.2014.00261
Hao, Enkui ; Mukhopadhyay, Partha ; Cao, Zongxian ; Erdélyi, Katalin ; Holovac, Eileen ; Liaudet, Lucas ; Lee, Wen Shin ; Haskó, G. ; Mechoulam, Raphael ; Pacher, Pál. / Cannabidiol protects against doxorubicin-induced cardiomyopathy by modulating mitochondrial function and biogenesis. In: Molecular Medicine. 2015 ; Vol. 21. pp. 38-45.
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