Lercanidipine inhibits vascular smooth muscle cell proliferation and neointimal formation via reducing intracellular reactive oxygen species and inactivating Ras-ERK1/2 signaling
Lercanidipine inhibits vascular smooth muscle cell proliferation and neointimal formation via reducing intracellular reactive oxygen species and inactivating Ras-ERK1/2 signaling
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DOI：
10.1016/j.phrs.2008.09.015
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发表时间：
2009-01-01
影响因子：
9.3
通讯作者：
Yeh, Jwu-Lai
中科院分区：
文献类型：
--
作者：
Wu, Jiunn-Ren;Liou, Shu-Fen;Yeh, Jwu-Lai
乐卡地平是一种钙通道拮抗剂，目前用于治疗原发性高血压和心绞痛。本研究的目的是阐明乐卡地平的抗增殖作用，并探讨这种药物的分子作用。采用离体实验和球囊损伤大鼠颈动脉模型研究乐卡地平对平滑肌细胞增殖的影响。用10%胎牛血清（FBS）和20 ng/ml血小板衍生生长因子（PDGF）-BB刺激大鼠血管平滑肌细胞（VSMC）培养物后，乐卡地平以剂量依赖性方式抑制VSMC增殖和迁移。FBS和PDGF-BB刺激的细胞内Ras、MEK 1/2、ERK 1/2、增殖细胞核抗原（PCNA）和Akt激活被乐卡地平显著抑制;然而，乐卡地平不影响FBS和PDGF-BB诱导的STAT 3磷酸化。乐卡地平还抑制PDGF-BB诱导的PDGF受体P链磷酸化和活性氧（ROS）的产生。在同步化细胞中，乐卡地平阻断FBS诱导的细胞周期通过G（0）/G（1）向S期的进展。在体内，球囊损伤后14天，用3和10 mg/kg乐卡地平治疗导致新生内膜/中膜比率的显著抑制。乐卡地平对新生内膜形成的抑制依赖于其对ERK 1/2磷酸化的影响。这些结果表明乐卡地平可以通过抑制细胞ROS、Ras-MEK 1/2-ERK 1/2和PI 3 K-Akt通路来抑制VSMCs的增殖，并提示其可能在预防人类再狭窄中具有治疗相关性。(C)2008爱思唯尔有限公司保留所有权利。
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 plate let-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 P 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. (C) 2008 Elsevier Ltd. All rights reserved.