Rajesh M, Mukhopadhyay P, Bátkai S, et al. Cannabidiol Attenuates Cardiac Dysfunction, Oxidative Stress, Fibrosis, and Inflammatory and Cell Death Signaling Pathways in Diabetic Cardiomyopathy. J Am Coll Cardiol 2010;56(25):2115-2125.
doi:10.1016/j.jacc.2010.07.033
http://content.onlinejacc.org/cgi/content/abstract/56/25/2115
http://content.onlinejacc.org/cgi/content/full/56/25/2115
http://content.onlinejacc.org/cgi/reprint/56/25/2115.pdf
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J Am Coll Cardiol, 2010; 56:2115-2125, doi:10.1016/j.jacc.2010.07.033
© 2010 by the American College of Cardiology Foundation
PRE-CLINICAL RESEARCH
Cannabidiol Attenuates Cardiac Dysfunction, Oxidative Stress, Fibrosis, and Inflammatory and Cell Death Signaling Pathways in Diabetic Cardiomyopathy
Mohanraj Rajesh, PhD*, Partha Mukhopadhyay, PhD*, Sándor Bátkai, MD, PhD*, Vivek Patel*, Keita Saito, PhD, Shingo Matsumoto, PhD, Yoshihiro Kashiwaya, MD, PhD, Béla Horváth, MD, PhD*, Bani Mukhopadhyay, PhD*, Lauren Becker*, György Haskó, MD, PhD, Lucas Liaudet, MD||, David A. Wink, PhD, Aristidis Veves, MD¶, Raphael Mechoulam, PhD# and Pál Pacher, MD, PhD*,*
* Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health, Bethesda, Maryland
Laboratory of Metabolic Control, NIAAA, National Institutes of Health, Bethesda, Maryland
Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Department of Surgery, University of Medicine and Dentistry, New Jersey–New Jersey Medical School, Newark, New Jersey
|| Department of Intensive Care Medicine, University Hospital, Lausanne, Switzerland
¶ Microcirculation Laboratory and Joslin-Beth Israel Deaconess Foot Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
# Department for Medicinal Chemistry and Natural Products, Faculty of Medicine, Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel
Manuscript received May 15, 2010; revised manuscript received July 5, 2010, accepted July 6, 2010.
* Reprint requests and correspondence: Dr. Pál Pacher, Section on Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, National Institutes of Health/NIAAA, 5625 Fishers Lane, MSC-9413, Bethesda, Maryland 20892-9413 (Email: pacher@mail.nih.gov).
Objectives: 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-B and mitogen-activated protein kinase (c-Jun N-terminal kinase, p-38, p38) activation, enhanced expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), tumor necrosis factor-, markers of fibrosis (transforming growth factor-?, 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-B 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.
Key Words: cannabinoids • diabetic complications • inflammation • oxidative stress