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-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion.
1 Section on Oxidative Stress Tissue Injury, Lab. Physiol. Studies, National Institutes of Health/NIAAA, Bethesda, Maryland, United States
2 Surgery, UMDNJ-New Jersey Medical School,, Newark, New Jersey, United States
3 Department of Intensive Care Medicine, University Hospital, 1011 Lausanne, Lausanne, VD, Switzerland
4 Howard L. Hunter Chemistry Laboratory, Clemson University, Clemson, South Carolina, United States
5 Physiology, New York Medical College, Valhalla, New York, United States
6 Physiology, New York Medical College, Valhalla, United States
7 Univ. of Washington, United States
8 Department of Pediatrics, Lipid Research Unit, Johns Hopkins University, Baltimore, Maryland, United States
* To whom correspondence should be addressed. E-mail: pacher{at}mail.nih.gov.
Targeting cannabinoid-2 (CB2) receptors with selective agonists may represent a novel therapeutic avenue in various inflammatory diseases, but the mechanisms by which CB2 activation exerts its anti-inflammatory effects and the cellular targets are elusive. Here we investigated the effects of CB2 receptor activation on TNF-
-induced signal transduction in human coronary artery endothelial cells (HCAECs) in vitro and on endotoxin-induced vascular inflammatory response in vivo. TNF- induced NF-
B and RhoA activation, up-regulation 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 the above mentioned effects of TNF- were attenuated by CB2 agonists. CB2 agonists also decreased the TNF-- and/or endotoxin-induced ICAM-1 and VCAM-1 expression in isolated aortas, and adhesion of monocytes to aortic vascular endothelium. CB1 and CB2 receptors were detectable in human coronary artery endothelial cells by western blotting, RT-PCR, real-time PCR and immunofluorescence staining. Since the above mentioned TNF--induced phenotypic changes are critical in the initiation and progression of atherosclerosis and restenosis our findings suggest that targeting CB2 receptors on endothelial cells may offer a novel approach in the treatment of these pathologies.
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