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Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis.
Mol Med 2015; 21:38-45MM

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+Show Affiliations

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.Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America.Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America.Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America.Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America.Department of Intensive Care Medicine, BH 08-621 University Hospital Medical Center, Lausanne, Switzerland.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.Departments of Surgery, Rutgers New Jersey Medical School, Newark, New Jersey, United States of America.Department for Medicinal Chemistry and Natural Products, Faculty of Medicine, Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel.Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, United States of America.

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

25569804

Citation

Hao, Enkui, et al. "Cannabidiol Protects Against Doxorubicin-Induced Cardiomyopathy By Modulating Mitochondrial Function and Biogenesis." Molecular Medicine (Cambridge, Mass.), vol. 21, 2015, pp. 38-45.
Hao E, Mukhopadhyay P, Cao Z, et al. Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis. Mol Med. 2015;21:38-45.
Hao, E., Mukhopadhyay, P., Cao, Z., Erdélyi, K., Holovac, E., Liaudet, L., ... Pacher, P. (2015). Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis. Molecular Medicine (Cambridge, Mass.), 21, pp. 38-45. doi:10.2119/molmed.2014.00261.
Hao E, et al. Cannabidiol Protects Against Doxorubicin-Induced Cardiomyopathy By Modulating Mitochondrial Function and Biogenesis. Mol Med. 2015 Jan 6;21:38-45. PubMed PMID: 25569804.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis. AU - Hao,Enkui, AU - Mukhopadhyay,Partha, AU - Cao,Zongxian, AU - Erdélyi,Katalin, AU - Holovac,Eileen, AU - Liaudet,Lucas, AU - Lee,Wen-Shin, AU - Haskó,György, AU - Mechoulam,Raphael, AU - Pacher,Pál, Y1 - 2015/01/06/ PY - 2014/12/22/received PY - 2014/12/23/accepted PY - 2015/1/9/entrez PY - 2015/1/9/pubmed PY - 2016/3/29/medline SP - 38 EP - 45 JF - Molecular medicine (Cambridge, Mass.) JO - Mol. Med. VL - 21 N2 - 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. SN - 1528-3658 UR - https://www.unboundmedicine.com/medline/citation/25569804/Cannabidiol_Protects_against_Doxorubicin_Induced_Cardiomyopathy_by_Modulating_Mitochondrial_Function_and_Biogenesis_ L2 - http://www.molmed.org/content/pdfstore/14_261_Hao.pdf DB - PRIME DP - Unbound Medicine ER -