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Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy.

Abstract

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-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.

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  • Authors+Show Affiliations

    ,

    Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892-9413, USA.

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    Source

    MeSH

    Animals
    Apoptosis
    Blood Glucose
    Body Weight
    Cannabidiol
    Cells, Cultured
    Diabetic Cardiomyopathies
    Disease Models, Animal
    Drug Evaluation, Preclinical
    Fibrosis
    Glucose
    Hemodynamics
    Humans
    Insulin
    MAP Kinase Signaling System
    Male
    Mice
    Mice, Inbred C57BL
    Myocardium
    Myocytes, Cardiac
    NF-kappa B
    Oxidative Stress
    Pancreas
    Reactive Oxygen Species

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, N.I.H., Intramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    21144973

    Citation

    TY - JOUR T1 - Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. AU - Rajesh,Mohanraj, AU - Mukhopadhyay,Partha, AU - Bátkai,Sándor, AU - Patel,Vivek, AU - Saito,Keita, AU - Matsumoto,Shingo, AU - Kashiwaya,Yoshihiro, AU - Horváth,Béla, AU - Mukhopadhyay,Bani, AU - Becker,Lauren, AU - Haskó,György, AU - Liaudet,Lucas, AU - Wink,David A, AU - Veves,Aristidis, AU - Mechoulam,Raphael, AU - Pacher,Pál, PY - 2010/05/15/received PY - 2010/07/05/revised PY - 2010/07/06/accepted PY - 2010/12/15/entrez PY - 2010/12/15/pubmed PY - 2011/4/6/medline SP - 2115 EP - 25 JF - Journal of the American College of Cardiology JO - J. Am. Coll. Cardiol. VL - 56 IS - 25 N2 - 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-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. SN - 1558-3597 UR - https://www.unboundmedicine.com/medline/citation/21144973/abstract/Cannabidiol_attenuates_cardiac_dysfunction_oxidative_stress_fibrosis_and_inflammatory_and_cell_death_signaling_pathways_in_diabetic_cardiomyopathy_ L2 - http://linkinghub.elsevier.com/retrieve/pii/S0735-1097(10)04190-2 ER -