Article: article from journal or magazin.
CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion.
American Journal of Physiology. Heart and Circulatory Physiology
Publication types: Journal Article
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.
Animals, Anti-Inflammatory Agents/pharmacology, Anti-Inflammatory Agents/therapeutic use, Aorta/drug effects, Aorta/metabolism, Cannabinoids/pharmacology, Cannabinoids/therapeutic use, Cells, Cultured, Chemokine CCL2/metabolism, Coronary Vessels/drug effects, Coronary Vessels/metabolism, Disease Models, Animal, Dose-Response Relationship, Drug, Endothelial Cells/drug effects, Endothelial Cells/metabolism, Humans, Inflammation/chemically induced, Inflammation/metabolism, Intercellular Adhesion Molecule-1/metabolism, Leukocyte Rolling/drug effects, Lipopolysaccharides, Male, Mice, Mice, Inbred C57BL, Monocytes/drug effects, Monocytes/metabolism, NF-kappa B/metabolism, RNA, Messenger/metabolism, Receptor, Cannabinoid, CB1/metabolism, Receptor, Cannabinoid, CB2/agonists, Receptor, Cannabinoid, CB2/genetics, Signal Transduction/drug effects, Tumor Necrosis Factor-alpha/metabolism, Vascular Cell Adhesion Molecule-1/metabolism, rhoA GTP-Binding Protein/metabolism
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