3种他汀药物调控纤溶活性抑制人血管平滑肌细胞增殖与迁移

 目的 探讨3种常用他汀药物(普伐他汀、辛伐他汀和氟伐他汀)介导纤溶酶原激活物及其抑制剂对体外培养人血管平滑肌细胞(VSMC)增殖和迁移的影响。方法 采用四唑盐(MTT)比色法测定VSMC增殖活性,刮伤实验和改良Transwell chamber装置测定细胞迁移能力;用RT-PCR分析细胞tPA,uPA和PAI-1 mRNA表达;采用发光底物法测定细胞分泌tPA和PAI-1蛋白含量。结果 辛伐他汀和氟伐他汀可通过下调细胞PAI-1 mRNA表达和上调tPA mRNA表达,抑制10％胎牛血清诱导VSMC增殖和迁移,不同他汀药物对纤溶活性的调控时相不尽相同。普伐他汀在指定时间对基因转录活性无影响,随培养时间延长对tPA和PAI-1蛋白分泌伴有轻度增加和抑制。结论　他汀类药物抑制VSMC增殖和迁移可能与非调脂性抗动脉粥样硬化作用机制有关,辛伐他汀和氟伐他汀通过上调tPA mRNA和下调PAI-1 mRNA基因转录活性,而普伐他汀可能与tPA和PAI-1通过翻译后修饰或与辅助因子相互作用而调控纤溶酶及其抑制物活性,进而促进纤溶,抑制细胞增殖和移行。

Effects of statins on the proliferation and migration of vascular smooth muscle cells by regulation of fibrinolysis

OBJECTIVE To investigate the potential inhibitory effects of three different statins on the proliferation and migrations of human vascular smooth muscle cells (VSMC) and to explore the cellular mechanism of their fibrinolytic activity.METHODS Human VSMC were incubated with different concentrations of statins in the presence of fetal bovine serum (FBS) as a survival factor. The presence of proliferation was evaluated by cell counting and MTT staining. The VSMC migration assays were performed using the wounding assay and the Transwell chamber apparatus. The expression of tissue plasminogen activator (tPA) mRNA and plasminogen activator inhibitor type-1 ( PAI-1) mRNA were analyzed by RT-PCR.tPA and PAI-1 activities were determined by colorimetric-substrate method. RESULTS Simvastatin and fluvastatin significantly down-regulated mRNA expression for PAI-1 in VSMC and up-regulated mRNA expression for tPA in VSMC and inhibited the proliferation and migration of VSMC induced with 10% FBS. The inhibitory effects of these two statins were dose-dependently. No significant effect of three statins on uPA mRNA expression in human VSMC was examined. Fluvastatin decreased PAI-1 activity and increased tPA protein activity in human VSMC by time-dependent mode. No effect of pravastatin on PAI-1 and tPA protein activities was examined in human VSMC incubated for 24 hours. CONCLUSION The results indicated that statins down-regulated PAI-1, which normally consumed tPA.In the absence of PAI-1,tPA activated plasminogen to generate plasmin.Thus, statins behave as antithrombotic agents and prothrombolytic agents.Furthermore statias might reduce fibrin formation and thrombus development.