title: Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy.
abstract: OBJECTIVE
  In this study, we have investigated the effects of cannabidiol (CBD) on myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type I diabetic cardiomyopathy and primary human cardiomyocytes exposed to high glucose.
  
  
  BACKGROUND
  Cannabidiol, the most abundant nonpsychoactive constituent of Cannabis sativa (marijuana) plant, exerts anti-inflammatory effects in various disease models and alleviates pain and spasticity associated with multiple sclerosis in humans.
  
  
  METHODS
  Left ventricular function was measured by the pressure-volume system. Oxidative stress, cell death, and fibrosis markers were evaluated by molecular biology/biochemical techniques, electron spin resonance spectroscopy, and flow cytometry.
  
  
  RESULTS
  Diabetic cardiomyopathy was characterized by declined diastolic and systolic myocardial performance associated with increased oxidative-nitrative stress, nuclear factor-κB and mitogen-activated protein kinase (c-Jun N-terminal kinase, p-38, p38α) activation, enhanced expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), tumor necrosis factor-α, markers of fibrosis (transforming growth factor-β, connective tissue growth factor, fibronectin, collagen-1, matrix metalloproteinase-2 and -9), enhanced cell death (caspase 3/7 and poly[adenosine diphosphate-ribose] polymerase activity, chromatin fragmentation, and terminal deoxynucleotidyl transferase dUTP nick end labeling), and diminished Akt phosphorylation. Remarkably, CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, nuclear factor-κB activation, and cell death in primary human cardiomyocytes.
  
  
  CONCLUSIONS
  Collectively, these results coupled with the excellent safety and tolerability profile of CBD in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications, and perhaps other cardiovascular disorders, by attenuating oxidative/nitrative stress, inflammation, cell death and fibrosis.
authors.affiliation: Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892-9413, USA.
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Rajesh
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Sándor
authors.initials: S
authors.lastname: Bátkai
authors.forename: Vivek
authors.initials: V
authors.lastname: Patel
authors.forename: Keita
authors.initials: K
authors.lastname: Saito
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kashiwaya
authors.forename: Béla
authors.initials: B
authors.lastname: Horváth
authors.forename: Bani
authors.initials: B
authors.lastname: Mukhopadhyay
authors.forename: Lauren
authors.initials: L
authors.lastname: Becker
authors.forename: György
authors.initials: G
authors.lastname: Haskó
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.forename: Aristidis
authors.initials: A
authors.lastname: Veves
authors.forename: Raphael
authors.initials: R
authors.lastname: Mechoulam
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002185:Cannabidiol / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005355:Fibrosis; D005947:Glucose; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D002185:Cannabidiol; D005947:Glucose