罗格列酮对高糖诱导的人血管内皮细胞纤溶系统的影响

Effects of Rosiglitazone on Fibrinolytic System of Endothelial Cells Induced by High Glucose

目的通过观察罗格列酮对高糖诱导的内皮细胞表达一氧化氮(NO)、组织纤溶酶原激活物(t-PA)和纤溶酶原激活物抑制物-1(PAI-1)的影响,探讨罗格列酮防止糖尿病患者冠脉支架术后再狭窄的机制。方法用不同浓度葡萄糖刺激体外培养的人肺静脉血管内皮细胞24 h,检测培养上清中NOt、-PA和PAI-1的含量;用10mmol/L浓度的葡萄糖和不同浓度的罗格列酮或二甲双胍干预共同体外培养的人肺静脉血管内皮细胞24 h后,检测NOt、-PA和PAI-1的含量。培养上清中NO采用硝酸还原酶法测定;t-PA和PAI-1采用酶联免疫法(ELISA)测定。结果随着葡萄糖浓度的升高,NO和t-PA的浓度呈下降的趋势,PAI-1的浓度呈升高趋势;罗格列酮干预后NO和t-PA的浓度呈升高趋势,PAI-1的浓度呈降低趋势;二甲双胍对这些指标无影响。结论高糖能刺激血管内皮细胞分泌NO、PAI-1,抑制t-PA的形成,从而引起凝血和纤溶的异常,这种高凝状态会促进血栓形成和再狭窄的发生;罗格列酮能抑制高糖引起的NO的降低,抑制高糖引起的内皮细胞的纤溶系统的平衡,促进纤溶系统的激活,防止血栓的形成,这可能是罗格列酮能减少糖尿病患者冠脉支架术后再狭窄的机制之一。

Objective The purposes of the study were to determine the effects of rosiglitazone on nitric oxide （NO）, tissue plasminogen activator （t-PA） and plasminogen activator inhibitor （PAI-1） expressed by endothelial ceils induced by high glucose. And the underlying mechanisms of rosiglitazone in prevention of restenosis after percutaneous transluminal coronary angioplasty（PTCA） in patients of diabetes is elucidated. Methods （1） Human vein endothelial cells exposed to high glucose and NO, t- PA,PAI-1 in supernatant were detected 24 hours later. （2） NO, t-PA, PAI-1 in supernatant of endothelial ceils were detected after intervened by glucose of 10 mmol/L, rosiglitazone and metformin for 24 hours. （3）NO in supernatant was assessed with revert enzymatic means of nitric acid ; t-PA and PAI-1 were measured by ELISA. Results The concentrations of NO, PAI-1 and t-PA of endothelial ceils intervened by glucose correlated to the level of glucose. Glucose blocked the productions of NO, t- PA and increased concentration of PAI-1. Glucose plus rosiglitazone increased the productions of NO, t-PA and reduced the concentration of PAI-1 compared with intervention only by glucose. And metformin had no effect. Conclusion （1） NO,PAI-1 expressed by endothelial cells can be induced and t-PA can be inhibited by high glucose. All these can cause dysfunctions of blood dotting and fibrinolytic system. This hypercoagulable state may promote thrombogenesis and restenosis after PTCA. （2） Rosiglitazone can inhibit the depression of NO induced by high glucose and hold back the dysfunctions of fibrinolytic system inspired by high glucose. It can promote the activation of fibrinolytic system and prevent thrombogenesis, which may be one of the mechanisms of rosiglitazone in prevention of restenosis after PTCA in patients of diabetes.