Role of CB2 cannabinoid receptors in interplay between endothelium and inflammatory cells: implications for ischemia‐reperfusion injury and atherosclerosis.

Abstract

Recently, targeting CB2 cannabinoid receptors with selective agonists may represent a novel therapeutic avenue in various inflammatory diseases, including atherosclerosis, but the mechanisms by which CB2 activation exerts its anti‐inflammatory and anti‐atherogenic effects and the cellular targets have remained elusive. We have studied the effects of CB2 receptor activation on TNF‐alpha‐induced signal transduction of human coronary artery endothelial and human liver sinusoidal endothelial cells (HCAECs and HLSECs) and on endotoxin‐induced vascular inflammatory responses in vivo, as well as in a mouse model of hepatic ischemiareperfusion injury. CB2 receptor activation with selective agonists attenuated TNF‐alpha‐triggered NF‐kappaB and Rho A activation, up‐regulation of ICAM‐1 and VCAM‐1, expression of monocyte chemoattractant protein in endothelial cells, transendothelial migration of monocytes, monocyte‐endothelial, and neutrophilendothelial adhesion in vitro, as well as the endotoxin‐induced vascular inflammatory response and ischemia‐reperfusion injury in vivo. The above mentioned endotoxin‐ and TNF‐alpha‐induced phenotypic changes are critical in the development of reperfusion injury, initiation and progression of atherosclerosis and restenosis, and cardiovascular aging, and may thus represent the mechanisms underlying the therapeutic effectiveness of CB2 receptor activation in these pathologies.