title: Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis.
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.
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America.|Department of Cardiology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China.
authors.forename: Enkui
authors.initials: E
authors.lastname: Hao
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Zongxian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Katalin
authors.initials: K
authors.lastname: Erdélyi
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Eileen
authors.initials: E
authors.lastname: Holovac
authors.affiliation: Department of Intensive Care Medicine, BH 08-621 University Hospital Medical Center, Lausanne, Switzerland.
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America.|Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Wen-Shin
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Departments of Surgery, Rutgers New Jersey Medical School, Newark, New Jersey, United States of America.
authors.forename: György
authors.initials: G
authors.lastname: Haskó
authors.affiliation: Department for Medicinal Chemistry and Natural Products, Faculty of Medicine, Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel.
authors.forename: Raphael
authors.initials: R
authors.lastname: Mechoulam
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D002185:Cannabidiol / Q000008:administration & dosage / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D066126:Cardiotoxicity; D016923:Cell Death; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects*; D004789:Enzyme Activation / Q000187:drug effects; D006439:Hemodynamics; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D002185:Cannabidiol; D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9