Cannabidiol protects against doxorubicin-induced cardiomyopathy by modulating mitochondrial function and biogenesis.

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 is a non-psychotropic constituent of marijuana, which is well-tolerated in humans, with antioxidant, anti-inflammatory, and recently discovered antitumor properties. We aimed to explore the effects of cannabidiol 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-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 gamma 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 cannabidiol markedly improved DOX-induced cardiac dysfunction, oxidative/nitrative stress and cell death. Cannabidiol also enhanced the DOX-induced impaired cardiac mitochondrial function and biogenesis. These data suggest that cannabidiol 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.