Chronic treatment with PDGF-BB and endothelin-1 synergistically induces vascular hyperplasia and loss of contractility in organ-cultured rat tail artery
Chronic treatment with PDGF-BB and endothelin-1 synergistically induces vascular hyperplasia and loss of contractility in organ-cultured rat tail artery
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DOI：
10.1016/j.atherosclerosis.2010.11.001
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发表时间：
2011-02-01
期刊：
影响因子：
5.3
通讯作者：
Ozaki, Hiroshi
中科院分区：
文献类型：
--
作者：
Kida, Taiki;Chuma, Hiroko;Ozaki, Hiroshi
目的：研究血小板源性生长因子- bb （PDGF-BB）和内皮素-1 （ET-1）在体外器官培养系统中对血管增生的协同作用。方法与结果：在器官培养的大鼠尾动脉中，100 ng/ml PDGF-BB和300nM ET-1同时处理4 d，诱导内侧增生，平滑肌细胞增殖增加。同时给予PDGF-BB （10-300 nM）和ET-1 （30nM-1 μ M）剂量依赖性地抑制高K+和去甲肾上腺素的收缩反应。这种收缩障碍伴随着α -肌动蛋白表达的降低。在所有系列实验中，PDGF-BB和ET-1联合治疗比PDGF-BB （100 ng/ml）或ET-1 （300 nM）单独治疗的效果更强。Western blot分析显示，PDGF-BB和ET-1联合治疗可协同磷酸化培养动脉细胞外信号调节激酶1和2 （ERK1/2）、Akt和哺乳动物雷帕霉素靶点（mTOR）下游靶点p70核糖体S6激酶。一致地，MAPK/ERK激酶（MEK）抑制剂PD98059 (30 μ M)，磷酸肌苷3-激酶（PI3K）抑制剂LY294002和mTOR抑制剂雷帕霉素（30 nM）部分恢复PDGF-BB和et -1诱导的增生性变化。结论：我们首次在组织水平上证明PDGF-BB和ET-1协同加速血管平滑肌增生改变并失去其收缩力，至少部分通过ERK1/2、Akt和mTOR激活。2010爱思唯尔爱尔兰有限公司版权所有。
Objective: In this study, we examined the synergistic effects of the two potent pathogenic factors, platelet-derived growth factor-BB (PDGF-BB) and endothelin-1 (ET-1) to induce vascular hyperplasia using ex vivo organ-culture system.Methods and results: In organ-cultured rat tail arteries, concomitant treatment with 100 ng/ml PDGF-BB and 300nM ET-1 for 4 days induced medial hyperplasia with increased smooth muscle cell proliferation. Concomitant treatment with PDGF-BB (10-300 nM) and ET-1 (30nM-1 mu M) dose-dependently suppressed contractile responses to high K+ and norepinephrine. This dyscontractility was accompanied by decreased alpha-actin protein expression. In all series of experiments, concomitant treatment with PDGF-BB and ET-1 exhibited stronger effects than sole treatment with PDGF-BB (100 ng/ml) or ET-1 (300 nM). Western blot analysis revealed that concomitant treatment with PDGF-BB and ET-1 synergistically phosphorylated extracellular signal-regulated kinase 1 and 2 (ERK1/2), Akt, and a downstream target of mammalian target of rapamycin (mTOR), p70 ribosomal S6 kinase in cultured artery. Consistently, a MAPK/ERK kinase (MEK) inhibitor, PD98059 (30 mu M), a phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, and an mTOR inhibitor, rapamycin (30 nM), partially restored PDGF-BB and ET-1-induced hyperplastic changes.Conclusions: We evidenced for the first time at tissue level that PDGF-BB and ET-1 synergistically accelerate vascular smooth muscle hyperplastic changes and lose its contractility, at least partially through ERK1/2, Akt, and mTOR activation. (C) 2010 Elsevier Ireland Ltd. All rights reserved.