Abstract
Targeting cannabinoid-2 (CB(2)) receptors with selective agonists may represent a novel therapeutic avenue in various inflammatory diseases, but the mechanisms by which CB(2) activation exerts its anti-inflammatory effects and the cellular targets are elusive. Here, we investigated the effects of CB(2)-receptor activation on TNF-alpha-induced signal transduction in human coronary artery endothelial cells in vitro and on endotoxin-induced vascular inflammatory response in vivo. TNF-alpha induced NF-kappaB and RhoA activation and upregulation of adhesion molecules ICAM-1 and VCAM-1, increased expression of monocyte chemoattractant protein, enhanced transendothelial migration of monocytes, and augmented monocyte-endothelial adhesion. Remarkably, all of the above-mentioned effects of TNF-alpha were attenuated by CB(2) agonists. CB(2) agonists also decreased the TNF-alpha- and/or endotoxin-induced ICAM-1 and VCAM-1 expression in isolated aortas and the adhesion of monocytes to aortic vascular endothelium. CB(1) and CB(2) receptors were detectable in human coronary artery endothelial cells by Western blotting, RT-PCR, real-time PCR, and immunofluorescence staining. Because the above-mentioned TNF-alpha-induced phenotypic changes are critical in the initiation and progression of atherosclerosis and restenosis, our findings suggest that targeting CB(2) receptors on endothelial cells may offer a novel approach in the treatment of these pathologies.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / pharmacology*
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Anti-Inflammatory Agents / therapeutic use
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Aorta / drug effects
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Aorta / metabolism
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Cannabinoids / pharmacology*
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Cannabinoids / therapeutic use
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Cells, Cultured
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Chemokine CCL2 / metabolism
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Coronary Vessels / drug effects
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Coronary Vessels / metabolism
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Endothelial Cells / drug effects*
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Endothelial Cells / metabolism
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Humans
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Inflammation / chemically induced
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Inflammation / metabolism
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Inflammation / prevention & control
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Intercellular Adhesion Molecule-1 / metabolism
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Leukocyte Rolling / drug effects*
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Lipopolysaccharides
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Male
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Mice
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Mice, Inbred C57BL
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Monocytes / drug effects*
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Monocytes / metabolism
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NF-kappa B / metabolism
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RNA, Messenger / metabolism
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Receptor, Cannabinoid, CB1 / metabolism
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Receptor, Cannabinoid, CB2 / agonists*
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Receptor, Cannabinoid, CB2 / genetics
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Receptor, Cannabinoid, CB2 / metabolism
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Signal Transduction / drug effects*
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Tumor Necrosis Factor-alpha / metabolism*
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Vascular Cell Adhesion Molecule-1 / metabolism
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rhoA GTP-Binding Protein / metabolism
Substances
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Anti-Inflammatory Agents
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CCL2 protein, human
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Cannabinoids
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Chemokine CCL2
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Lipopolysaccharides
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NF-kappa B
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RNA, Messenger
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Receptor, Cannabinoid, CB1
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Receptor, Cannabinoid, CB2
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Tumor Necrosis Factor-alpha
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Vascular Cell Adhesion Molecule-1
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Intercellular Adhesion Molecule-1
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HU 308
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rhoA GTP-Binding Protein
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1,1-dimethylbutyl-1-deoxy-Delta(9)-THC