title: Lercanidipine inhibits vascular smooth muscle cell proliferation and neointimal formation via reducing intracellular reactive oxygen species and inactivating Ras-ERK1/2 signaling.
abstract: Lercanidipine, a calcium channel antagonist, is currently employed in the treatment of essential hypertension and angina pectoris. The purpose of this study was to elucidate the anti-proliferative effect of lercanidipine and to investigate the molecular role of this agent. Both in vitro studies and in a balloon injury rat carotid artery model were employed to study the effect of lercanidipine on smooth muscle cell proliferation. Lercanidipine-inhibited rat vascular smooth muscle cell (VSMC) proliferation and migration in a dose-dependent manner following stimulation of VSMC cultures with 10% fetal bovine serum (FBS) and 20 ng/ml platelet-derived growth factor (PDGF)-BB. FBS- and PDGF-BB-stimulated intracellular Ras, MEK1/2, ERK1/2, proliferative cell nuclear antigen (PCNA), and Akt activations were significantly inhibited by lercanidipine; however, lercanidipine did not affect FBS- and PDGF-BB-induced STAT3 phosphorylation. Lercanidipine also inhibited PDGF-receptor beta chain phosphorylation and reactive oxygen species (ROS) production induced by PDGF-BB. Lercanidipine blocked the FBS-inducible progression through the G(0)/G(1) to the S-phase of the cell cycle in synchronized cells. In vivo, 14 days after balloon injury, treatment with 3 and 10 mg/kg lercanidipine resulted in significant inhibition of the neointima/media ratio. Suppression of neointima formation by lercanidipine was dependent on its influence on ERK1/2 phosphorylation. These results demonstrate that lercanidipine can suppress the proliferation of VSMCs via inhibiting cellular ROS, Ras-MEK1/2-ERK1/2, and PI3K-Akt pathways, and suggesting that it may have therapeutic relevance in the prevention of human restenosis.
authors.affiliation: Division of Pediatric Pulmonology and Cardiology, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Jiunn-Ren
authors.initials: JR
authors.lastname: Wu
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Liou
authors.forename: Shin-Wha
authors.initials: SW
authors.lastname: Lin
authors.forename: Chee-Yin
authors.initials: CY
authors.lastname: Chai
authors.forename: Zen-Kong
authors.initials: ZK
authors.lastname: Dai
authors.forename: Jyh-Chong
authors.initials: JC
authors.lastname: Liang
authors.forename: Ing-Jun
authors.initials: IJ
authors.lastname: Chen
authors.forename: Jwu-Lai
authors.initials: JL
authors.lastname: Yeh
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D010982:Platelet-Derived Growth Factor; D018809:Proliferating Cell Nuclear Antigen; D020574:Proto-Oncogene Proteins c-sis; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D000077214:Becaplermin; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; C060343:lercanidipine