CB2 receptor agonists attenuate TNF‐α induced human vascular smooth muscle cell proliferation and migration

Abstract

Vascular smooth muscle proliferation and migration triggered by inflammatory stimuli are involved in the development and progression of atherosclerosis and restenosis. Cannabinoids may modulate cell proliferation in various cell types through cannabinoid 2 (CB2) receptors. Herein, we have investigated the effects of CB2 receptor agonists on TNF‐alpha‐induced proliferation, migration and signal transduction in human coronary artery smooth muscle cells (HCASMCs). HCASMCs were stimulated with TNF‐alpha and smooth muscle cell proliferation was determined by the extent of BrdU incorporation and the migration was assayed. CB2 and/or CB1 receptor expressions were determined by immunoflourescence staining, western, RT‐PCR, real‐time PCR and flow cytometry. Moderate levels of CB2 and CB1 receptors were detectable in HCASMCs compared to the very high levels of CB2 receptors expressed in THP‐1 monocytes. TNF‐alpha triggered up to ∼2.5 fold increase in CB2 receptor mRNA expression and/or protein expression in HCASMCs. Further, TNF‐alpha induced Ras, p38 MAPK, ERK ½, Akt and SAPK/JNK activation, with concordant increase in the proliferation and migration of smooth muscle cells. The CB2 agonists, JWH133 and HU308, dose‐dependently attenuated these effects of TNF‐alpha. Since the above‐mentioned TNF‐alpha‐induced phenotypic changes are critical in the initiation and progression of atherosclerosis and restenosis our findings suggest that CB2 agonists may offer a novel approach in the treatment of these pathologies by decreasing vascular smooth muscle proliferation and migration.