In this study we demonstrate that a selective CB1 receptor antagonist attenuates PDGF–induced proliferation and migration of human coronary artery smooth muscle cells and the activation of various interrelated signaling pathways (Ras and ERK 1/2).
Previous studies have attributed pivotal role for platelet-derived growth factor (one of the main triggers involved in promoting vascular smooth muscle proliferation and migration) in the development of various vascular disorders such as atherosclerosis and restenosis following vascular injury and/or percutaneous transluminal angioplasty [6
]. Recent studies have reported that CB1
inhibition in human peripheral blood mononulclear, human breast cancer cells, and NIH3T3 fibroblasts results in inhibition of the cell proliferation and migration and/or apoptosis mediated via inhibition of ERK1/2 and interrelated signaling pathways [20
inhibition also attenuates doxorubicin-induced cell death in cardiomyocytes, which may also involve ERK1/2 activation [24
]. Furthermore CB1
antagonist rimonabant also inhibits inflammatory cell migration and attenuates the development of atherosclerosis in a mouse model of disease [15
], in addition to the reduction of the percent of atheroma volume in patients [14
]. On the basis of the above mentioned studies and the accumulating evidence suggesting that CB1
activation involves MAPK signaling (e.g. ERK1/2 activation) in various cell types, we hypothesized that CB1
receptor blockade in vascular smooth muscle cells may attenuate PDGF-induced cell migration and proliferation. Indeed, as shown in and , CB1
receptor inhibition with rimonabant concentration-dependently attenuated PDGF-induced, but not basal coronary artery vascular smooth muscle cell proliferation (measured by BrdU incorporation), as well as cell migration, without affecting PDGF-induced PDGFR-β activation. CB1
antagonist also attenuated the activation of the PDGF-induced signaling cascade (ERK1/2 and Ras activation) involved in vascular smooth muscle cell proliferation and migration ().
Collectively, our results demonstrate that CB1 inhibition with rimonabant attenuates PDGF-induced Ras and ERK 1/2 activation, while decreasing proliferation and migration of HCASMCs. These findings forecast that in addition to improving plasma lipid alterations and decreasing inflammatory cell migration and inflammatory response, CB1 antagonists may exert beneficial effects in atherosclerosis and restenosis by decreasing vascular smooth muscle proliferation and migration.