CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion

Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2210-8. doi: 10.1152/ajpheart.00688.2007. Epub 2007 Jul 27.

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

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

MeSH terms

  • 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
  • Inflammation / prevention & control
  • 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
  • Receptor, Cannabinoid, CB2 / metabolism
  • Signal Transduction / drug effects*
  • Tumor Necrosis Factor-alpha / metabolism*
  • Vascular Cell Adhesion Molecule-1 / metabolism
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Anti-Inflammatory Agents
  • CCL2 protein, human
  • Cannabinoids
  • Chemokine CCL2
  • Lipopolysaccharides
  • NF-kappa B
  • RNA, Messenger
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • HU 308
  • rhoA GTP-Binding Protein
  • 1,1-dimethylbutyl-1-deoxy-Delta(9)-THC