Isoeugenodilol inhibits smooth muscle cell proliferation and neointimal thickening after balloon injury via inactivation of ERK1/2 pathway.
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 beta-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 G(0)/G(1) 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 Ca(2+) 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.
Yeh
Jwu-Lai
JL
Department and Graduate Institute of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Liou
Shu-Fen
SF
Chang
Yu-Pay
YP
Lin
Shin-Wha
SW
Liu
Ts'an-Shiun
TS
Wu
Bin-Nan
BN
Chen
Ing-Jun
IJ
Wu
Jiunn-Ren
JR
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005054:Eugenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries; D010766:Phosphorylation; D051381:Rats; D017539:Tunica Intima / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries
D004791:Enzyme Inhibitors; C121554:eugenodilol; D005054:Eugenol; D020928:Mitogen-Activated Protein Kinases