阿托伐他汀抑制C反应蛋白对肺动脉平滑肌细胞的增殖作用研究

The Effects of atrovastatin on pulmonary artery smooth cells proliferation induced by C-reactive protein

目的近年的研究显示,炎症参与肺动脉高压的发生和发展。作为炎症的重要指标,C反应蛋白(CRP)是肺动脉高压的独立预测因子。本文通过观察CRP和阿托伐他汀对培养的肺动脉平滑肌细胞(hPASMCs)增殖的影响,探讨CRP和阿托伐他汀对肺血管疾病的可能作用。方法体外培养hPASMCs,以不同浓度的CRP(5-200μg/ml)刺激24h,或先加阿托伐他汀(0.1-10μmol/l)处理2h。核因子κB(NF-κB)的活性以非变性凝胶电泳迁移率(EMSA)方法进行分析。细胞增殖水平以5-溴脱氧尿嘧啶核苷(BrDU)掺入法和ELISA方法进行检测。结果 CRP刺激hPASMCs的增殖程度呈浓度依赖性,随着CRP浓度的增加,细胞增殖倍数逐渐上升,在CRP200μg/ml组,其增殖倍数为对照组的1.84±0.12(P<0.001)。CRP显著诱导NF-κB在hPASMCs中的激活。阿托伐他汀则通过抑制NF-κB的激活而减轻hPASMCs的增殖。结论 CRP促进肺动脉平滑肌细胞的增殖,具有浓度依赖性,这一作用是通过对NF-κB的核内转位激活而介导的。提示CRP在肺动脉高压的发病中有重要作用,阿托伐他汀可能对肺血管疾病有保护作用。

Objective Several recent studies have shown that inflammation may play an important role in pulmonary artery hypertension （PAH）, and C-reactive protein （CRP） is an independent predictor of pulmonary artery disease. We, therefore, examined the impact and the possible mecha- nisms of CRP and atorvastatin on proliferation in cultured human pulmonary artery smooth muscle cells （hPASMCs）. Mehtods Human PASMCs were cultured and stimulated by a variety of concemtration of CRP （5-200p, g/ml） for 24h. Atorvastatin （0.1-10gmol/l） was pre-incubated for 2h with cells in the presence of CRP. The activity of nuclear factor-r,B （NF-r,B） was evaluated by electrophoretic mobility shift assay （EMSA）. hPASMCs prolifera- tion levels were measured by BrDU incorporation assay. Results （1） CRP induced the proliferation of hPASMCs as a dose-dependent manner. The proliferation fold over control was 1.84±0.12 in CRP 200pg/ml. （2） CRP significantly induced the activation of NF-~cB in hPASMCs. Pre-incubation of 0.1-10p.mol/1 atorvastatin significantly decreased the proliferation induced by CRP by means of attenuating the activation of NF-KB. Conclusions CRP induced the proliferation of hPASMCs in vitro, which was mediated by NF-kB translocation. These data offer important insights into the role of CRP in the pathogenesis of pulmonary hypertension, and suggest atorvastatin may have protective effects on pulmonary vascular disease.