Isoeugenodilol inhibits smooth muscle cell proliferation and neointimal thickening after balloon injury via inactivation of ERK1/2 pathway |
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Authors: | Jwu-Lai Yeh Shu-Fen Liou Yu-Pay Chang Shin-Wha Lin Ts’an-Shiun Liu Bin-Nan Wu Ing-Jun Chen Jiunn-Ren Wu |
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Affiliation: | (1) Department and Graduate Institute of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;(2) Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan;(3) Department of Anatomy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;(4) Division of Pediatric Pulmonology and Cardiology, Department of Pediatrics, Kaohsiung Medical University Hospital, No 100 Shih-Chuan 1st Road, Kaohsiung, 807, Taiwan;(5) Department of Clinical Laboratory, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan |
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Abstract: | The purpose of this study was to determine the efficacy and the possible mechanism of action of the synthesized drug isoeugenodilol (a new third-generation β-adrenoceptor blocker) on the growth factor-induced proliferation of cultured rat vascular smooth muscle cells (VSMCs) and neointimal formation in a rat carotid arterial balloon injury model. Isoeugenodilol significantly inhibited 10% FBS, 20 ng/ml PDGF-BB, and 20 ng/ml vascular endothelial growth factor (VEGF)-induced proliferation. In accordance with these findings, isoeugenodilol revealed blocking of the FBS-inducible progression through the G0/G1 to the S phase of the cell cycle in synchronized cells. Neointimal formation, measured 14 days after injury, was reduced by the oral administration of isoeugenodilol (10 mg/kg/day). In an in vitro assay, isoeugenodilol inhibited the migration of VSMCs stimulated by PDGF-BB. These findings indicate that isoeugenodilol shows an inhibitory potency on neointimal formation due to inhibition of both migration and proliferation of VSMCs. In addition, isoeugenodilol in concentration-dependent manner decreased the levels of phosphorylated ERK1/2 in both VSMCs and balloon-injured carotid arteries. The levels of phosphorylated MEK1/2 and Pyk2 as well as intracellular Ca2+ and reactive oxygen species (ROS) were in concentration-dependent manner reduced by isoeugenodilol. Taken together, these results indicate that isoeugenodilol may suppress mitogen-stimulated proliferation and migration partially through inhibiting cellular ROS and calcium, and hence, through activation of the Pyk2-ERK1/2 signal pathway. This suggests that isoeugenodilol has potential for the prevention of atherosclerosis and restenosis. |
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Keywords: | α -/β -Adrenoceptor blockade Vascular smooth muscle cell Restenosis Migration MAP kinase Calcium Reactive oxygen species |
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