非甾体抗炎药抑制大鼠血管平滑肌细胞增殖  

INHIBITION OF VASCULAR SMOOTH MUSCLE CELL PROLIFERATION BY NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

作　　者：王跃群[1] Brooks Gavin Harper Jane 李永青[1] 朱传炳[1] 袁婺洲[1] 吴秀山[1] 

机构地区：[1]湖南师范大学生命科学学院蛋白质化学及发育生物学教育部重点实验室,长沙410081 [2]英国雷丁大学动物及微生物系

出　　处：《实验生物学报》2003年第2期85-90,共6页Acta Biologiae Experimentalis Sinica

基　　金：国家自然科学基金(No:30170479);湖南省特聘教授基金(25000613);国家留学基金

摘　　要：本文研究了aspirin、ibuprofen和sulindac三种不同结构的非甾体抗炎药(NSAID)对大鼠A10血管平滑肌细胞(VSMC)增殖的影响并探讨其作用机制。方法:细胞计数法观察不同浓度的三种NSAID对细胞增殖的影响,乳酸脱氢酶(LDH)释放分析法测定NSAID的细胞毒作用,流式细胞术分析测定细胞周期。结果:aspirin、ibuprofen和sulindac三种NSAID都对A10 VSMC的增殖有明显抑制作用,且其作用是浓度依赖性的,IC_(50)分别是:aspirin为1666μmol/L,ibuprofen为937μmol/L,sulindac为520μmol/L;其抑制作用不是因细胞毒作用引起;三种NSAID对细胞周期的作用不同,ibuprofen(1000μmol/L)和sulindac(750μmol/L)将细胞阻抑在细胞周期的G_1期(从68.7±2.0%上升到76.6±2.2%和75.8±2.2%,P<0.05),而aspirin(2500μmol/L)对处于细胞周期各期的细胞百分率无明显改变;利用有丝分裂抑制剂nocodazole辅助分析,更清楚地检测到了ibuprofen和sulindac在G_1阻抑,而aspirin仍然不引起处于细胞周期各期的细胞百分率的明显改变。结论:aspirin抗A10 VSMC的增殖作用机制与ibuprofen和sulindac两者的作用机制不同,本研究为三种NSAID成为VSMC增殖性疾病的治疗药物提供了理论依据。Abnormal vascular smooth muscle cell (VSMC) proliferation is known to play an important role in the pathogenesis of atherosclerosis, restenosis and instent stenosis. Recent studies suggest that salicylates, in addition to inhibiting cyclooxygenase activity, exert an antiproliferative effect on VSMC growth both in vitro and in vivo. However, whether all non-steroidal anti-inflammatory drugs (NSAID) exert similar antiproliferative effects on VSMCs, and do so via a common mechanism of action, remains unknown. In the present study, we demonstrated that the NSAIDs, aspirin, ibuprofen and sulindac induced a dose-dependent inhibition of proliferation in rat A10 VSMCs (IC50 = 1666μmol/L, 937μmol/L and 520μmol/L, respectively). These drugs did not show significant cytotoxic effects as determined by LDH release assay, even at the highest concentrations tested (aspirin, 5000μmol/L; ibuprofen, 2500μmol/L; and sulindac, 1000μmol/L). Flow cyto-metric analyses showed that a 48 h exposure of A10 VSMCs to ibuprofen (1000μmol/L) and sulindac (750μmol/L) led to a significant Gt arrest (from 68.7±2.0% of cells in G1 to 76.6±2.2% and 75.8±2.2 % , respectively, p<0.05). In contrast, aspirin (2500μmol/L) failed to induce a significant G1 arrest (68.1 ±5.2%). Clearer evidence of a G1 block was obtained by treatment of cells with the mitotic inhibitor, noco-dazole (40ng/ml), for the final 24h of the experiment. Under these conditions, aspirin still failed to induce a G1 arrest (from 25.9±10.9 % of cells in G1 to 19.6±2.3%) whereas ibuprofen and sulindac led to a significant accumulation of cells in G1(51.8%±17.2% and 54.1%±10.6% , respectively, p<0.05). These results indicate that ibuprofen and sulindac inhibit VSMC proliferation by arresting the cell cycle in the G1 phase whereas the effect of aspirin appears to be independent of any special phase of the cell cycle. Irrespective of mechanism, our results suggest that NSAIDs might be of benefit to the treatment of vascular proliferative disorders.

关 键 词：血管平滑肌 非甾体抗炎药 细胞增殖 作用机制 抑制作用 浓度依赖性 细胞周期 流式细胞分析 冠状动脉疾病 

分 类 号：R541.4[医药卫生—心血管疾病] R978[医药卫生—内科学]