他汀对高糖情况下微血管纤溶酶原激活物抑制物-1产生的影响及其信号机制的研究
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摘要
血管病变是糖尿病最严重的并发症，大多数糖尿病患者死于心脑血管动脉粥样硬化和糖尿病肾病。糖尿病微血管病变患者发生心血管事件的风险显著增高，因此，对
2型糖尿病微血管病变进行关注和研究，对于防治大血管事件，减少患者死亡率显得极为重要。纤溶蛋白溶解系统活性异常是糖尿病微血管并发症的因素之一，其中最重要的纤溶抑制物是纤溶酶原激活抑制物-1（plasminogen activator inhibitor, PAI-1）。PAI-1是联系着心脑血管疾病发生发展的重要分子。
他汀除了降脂以外还具有其他方面的有益作用，如促纤溶、改善内皮功能及抗凝聚等作用。他汀是否对糖尿病微血管并发症患者的纤溶功能产生更多的获益作用，他汀又是通过什么机制产生促纤溶效应的，这些问题是本项研究的主要内容。
目的：观察辛伐他汀对2型糖尿病（T2DM）有或无微血管并发症患者纤溶酶原激活物抑制物-1（PAI-1）水平的影响。
方法：研究129例2型糖尿病，包括50例单纯糖尿病及79例糖尿病微血管并发症以及56例正常对照，ELISA法测定血浆PAI-1的水平，并随访糖尿病伴或不伴微血管并发症患者服用或不服用辛伐他汀3个月后PAI-1值的变化。并同时检测一般血脂、血糖生化指标。
结果：与正常对照相比，糖尿病组PAI-1水平显著增高（P<0.01），糖尿病微血管并发症组PAI-1水平显著高于单纯糖尿病组（P<0.01）。具有1种微血管并发症与同时合并2种或以上微血管并发症的患者相比，PAI-1水平无差异。2型糖尿病患者辛伐他汀治疗3个月均比治疗前PAI-1水平显著降低，其中微血管并发症组服
用他汀3个月后PAI-1值较未服他汀的微血管并发症组显著降低，并且降低程度大于他汀治疗的单纯糖尿病组。
结论：2型糖尿病患者存在纤溶功能受损，其中合并微血管并发症者纤溶功能受损较单纯糖尿病更为严重。辛伐他汀显著改善了纤溶功能，微血管并发症患
者服用辛伐他汀对纤溶功能的改善更为获益。
目的比较酶消化法和组织块贴壁法分离成年大鼠心脏微血管内皮细胞的方法并进行改良，以获得较高纯度和活性的细胞。
方法分别采用组织块贴壁法和酶消化法分离大鼠心脏微血管内皮细胞，并对方法进行改良。对分离传代的细胞进行表面特异性抗原CD31免疫荧光鉴定。
结果两种方法都获得了心脏微血管内皮细胞，CD31鉴定细胞阳性率在95%以上。两种方法相比，酶消化法具有获得所需的细胞时间相对短，稳定可靠，细胞纯度高等特点。
结论使用酶消化法可获得纯度高、状态良好的心脏微血管内皮细胞，该法培养的细胞可用于后续试验。
目的：通过研究辛伐他汀和阿托伐他汀抑制高糖诱导心脏微血管内皮细胞（CMEC）PAI-1表达的影响，探讨他汀调控高糖诱导CMEC表达PAI-1的信号机制。
方法：原代培养大鼠心脏微血管内皮细胞，在含糖5.7mM至23mM的培养基作用下，Real-time PCR法测定PAI-1mRNA的表达，ELISA和western blot法分别测定培养上清及内皮细胞PAI-1蛋白含量。Pull down法测定RhoA的活性，western blot测定IκBα的蛋白表达，凝胶电泳迁移率（EMSA）测定IκBα的活化，双荧光素酶报告基因测定IκBα的转录活性。
结果：PAI-1mRNA及蛋白水平随着培养基糖浓度的升高而升高，但是辛伐他汀及阿托伐他汀能显著抑制该效应（P<0.01），并且抑制效应可被甲羟戊酸（MVA，100μm）及焦磷酸牛龙牛儿基牛龙牛儿酯（GGPP，10μm）逆转，而不能被焦磷酸法尼酯（FPP，10μm）所逆转。RhoA抑制剂C3胞外酶（5μg/mL）、RhoA激酶抑制剂Y-27632（10μm）、羟基法舒地尔（10μm）及NF-κB抑制剂BAY11-7082（5μm）可产生类似他汀对PAI-1的抑制效应。高糖诱导CMEC RhoA及NF-κB激活均被2种他汀显著抑制（P<0.01）。辛伐他汀与阿托伐他汀对高糖情况下PAI-1表达的抑制作用无差异。
结论：辛伐他汀及阿托伐他汀抑制高糖诱导PAI-1表达的效应可能部分通过RhoA/ROCK-NF-κB旁路调控。辛伐他汀与阿托伐他汀对高糖诱导PAI-1表达的抑制程度无差异。代谢综合征病人可能因他汀的多向性作用而有更多获益。
Vascular diseases are the most serious complications of diabetes, most diabeticpatients died of cardiovascular and cerebrolvascular atherosclerosis and diabeticnephropathy. The risk of cardiovascular events is significantly higher in diabetic patients
with microvascular complications. Therefore, it’s extremely important to call for morefocus and studies on microvascular complications of type2diabetes to prevent majorvascular events and induce mortality. The abnormity of fibrinolytic system plays animportant role in diabetic complications. The most important fibrinolytic inhibitor isplasminogen activator (PAI-1) which is linked to the onset and development ofcardiovascular and cerebrolvascular diseases.
Statins has multifunctional benifits except lipid lowing such as fibrinolysis, improvingendothelial function and antithrombin effect, etc. Whether diabetic patients withmicrovascular complications could benefit more from statins treatment by improvingfibrinolysis and the mechanism of fibrinolytic effects of statins deserves further studies.That’s the main content of this study.
Objective The aim of our study was to compare the effect of simvastatin on reducingplasma plasminogen activator inhibitor-1levels in diabetic patients with or withoutmicrovascular complications.
Methods We enrolled129type2diabetic patients with (n=79) and without (n=50) diabetic microvascular complications and56control subjects. Plasma PAI-1levels weremeasured by ELISA before and after3months simvastatin treatment in18diabetic patientswith and17without microvascular complications. Common lipid and glucose metabolicparameters were also measured.
Results Diabetic patients have higher PAI-1lever compared with matched healthysubjects, and those with microvascular complications exhibited significantly higher levelsof PAI-1than those without. Plasma PAI-1levels were significantly reduced after3monthstreatment of simvastatin. The degree of reduction of PAI-1in group of microvascularcomplications was greater than that of group of diabetes without microvascularcomplications.
Conclusion Type2diabetes exhibited impaired fibrinolytic function, and more severeimpairment observed in group with microvascular complications. Therapy with simvastatinimproved fibrinolytic function，thus diabetic patients with microvascular complicationsbenefit more compared with those without microvascular complications.
Objective This study was to compare two methods of isolating adult rat cardiacmicrovascular endothelial cells (CMEC) and improve the methods.
Methods We use tissue adhere method and enzyme digestion procedure respectivelyto isolate CMEC. Immunofluorescence assay was used to identify specific expression ofCD31on the surface of CMEC.
Results We isolated CMEC successfully by these two different methods. The positiverates of CD31were no less than95%. The method of enzyme digestion not only has theadvantage of shorter time to gain a certain amount of cells, it is also a stable procedure toget relatively higher purity of cells compared to tissue adhere method.
Conclusion We recommend using the method of enzyme digestion to obtain highpurity CMEC in good condition.
Objective The aim of this study was to investigate the possible proinflammatorysignaling pathways involved in statin inhibition of glucose-induced plasminogen activatorinhibitor-1(PAI-1) expression in cardiac microvascular endothelial cells (CMECs).
Methods Primary rat CMECs were grown in the presence of5.7mmol/L or23mmol/L glucose. PAI-1mRNA and protein expression levels were measured by real-timePCR and ELISA, respectively. A pull-down assay was performed to determine RhoAactivity. IκBα protein expression was measured by western blotting, and NF-κBtranscription activity was determined by a dual luciferase reporter gene assay.
Results PAI-1mRNA and protein expression levels were both increased with highglucose concentrations, but they were significantly suppressed by simvastatin andatorvastatin treatment (P<0.01) and the effects were reversed by mevalonate (MVA,100μM) and geranylgeranyl pyrophosphate (GGPP,10μM) but not farnesyl pyrophosphate(FPP,10μM). Such effects were similar to those of a RhoA inhibitor, C3exoenzyme (5μg/mL), inhibitors of RhoA kinase (ROCK), Y-27632(10μmol/L) and hydroxyfasudil (10μmol/L), and a NF-κB inhibitor, BAY11-7082(5μmol/L). High glucose-induced RhoAand NF-κB activations in CMECs were both significantly inhibited by statins (P<0.01).Simvastatin and atorvastatin equally suppress high glucose-induced PAI-1expression.
Conclusion These effects of statins may occur partly by regulating theRhoA/ROCK-NF-κB pathway. The multifunctional roles of statins may be particularlybeneficial for patients with metabolic syndrome.
2型糖尿病微血管病变进行关注和研究，对于防治大血管事件，减少患者死亡率显得极为重要。纤溶蛋白溶解系统活性异常是糖尿病微血管并发症的因素之一，其中最重要的纤溶抑制物是纤溶酶原激活抑制物-1（plasminogen activator inhibitor, PAI-1）。PAI-1是联系着心脑血管疾病发生发展的重要分子。
他汀除了降脂以外还具有其他方面的有益作用，如促纤溶、改善内皮功能及抗凝聚等作用。他汀是否对糖尿病微血管并发症患者的纤溶功能产生更多的获益作用，他汀又是通过什么机制产生促纤溶效应的，这些问题是本项研究的主要内容。
目的：观察辛伐他汀对2型糖尿病（T2DM）有或无微血管并发症患者纤溶酶原激活物抑制物-1（PAI-1）水平的影响。
方法：研究129例2型糖尿病，包括50例单纯糖尿病及79例糖尿病微血管并发症以及56例正常对照，ELISA法测定血浆PAI-1的水平，并随访糖尿病伴或不伴微血管并发症患者服用或不服用辛伐他汀3个月后PAI-1值的变化。并同时检测一般血脂、血糖生化指标。
结果：与正常对照相比，糖尿病组PAI-1水平显著增高（P<0.01），糖尿病微血管并发症组PAI-1水平显著高于单纯糖尿病组（P<0.01）。具有1种微血管并发症与同时合并2种或以上微血管并发症的患者相比，PAI-1水平无差异。2型糖尿病患者辛伐他汀治疗3个月均比治疗前PAI-1水平显著降低，其中微血管并发症组服
用他汀3个月后PAI-1值较未服他汀的微血管并发症组显著降低，并且降低程度大于他汀治疗的单纯糖尿病组。
结论：2型糖尿病患者存在纤溶功能受损，其中合并微血管并发症者纤溶功能受损较单纯糖尿病更为严重。辛伐他汀显著改善了纤溶功能，微血管并发症患
者服用辛伐他汀对纤溶功能的改善更为获益。
目的比较酶消化法和组织块贴壁法分离成年大鼠心脏微血管内皮细胞的方法并进行改良，以获得较高纯度和活性的细胞。
方法分别采用组织块贴壁法和酶消化法分离大鼠心脏微血管内皮细胞，并对方法进行改良。对分离传代的细胞进行表面特异性抗原CD31免疫荧光鉴定。
结果两种方法都获得了心脏微血管内皮细胞，CD31鉴定细胞阳性率在95%以上。两种方法相比，酶消化法具有获得所需的细胞时间相对短，稳定可靠，细胞纯度高等特点。
结论使用酶消化法可获得纯度高、状态良好的心脏微血管内皮细胞，该法培养的细胞可用于后续试验。
目的：通过研究辛伐他汀和阿托伐他汀抑制高糖诱导心脏微血管内皮细胞（CMEC）PAI-1表达的影响，探讨他汀调控高糖诱导CMEC表达PAI-1的信号机制。
方法：原代培养大鼠心脏微血管内皮细胞，在含糖5.7mM至23mM的培养基作用下，Real-time PCR法测定PAI-1mRNA的表达，ELISA和western blot法分别测定培养上清及内皮细胞PAI-1蛋白含量。Pull down法测定RhoA的活性，western blot测定IκBα的蛋白表达，凝胶电泳迁移率（EMSA）测定IκBα的活化，双荧光素酶报告基因测定IκBα的转录活性。
结果：PAI-1mRNA及蛋白水平随着培养基糖浓度的升高而升高，但是辛伐他汀及阿托伐他汀能显著抑制该效应（P<0.01），并且抑制效应可被甲羟戊酸（MVA，100μm）及焦磷酸牛龙牛儿基牛龙牛儿酯（GGPP，10μm）逆转，而不能被焦磷酸法尼酯（FPP，10μm）所逆转。RhoA抑制剂C3胞外酶（5μg/mL）、RhoA激酶抑制剂Y-27632（10μm）、羟基法舒地尔（10μm）及NF-κB抑制剂BAY11-7082（5μm）可产生类似他汀对PAI-1的抑制效应。高糖诱导CMEC RhoA及NF-κB激活均被2种他汀显著抑制（P<0.01）。辛伐他汀与阿托伐他汀对高糖情况下PAI-1表达的抑制作用无差异。
结论：辛伐他汀及阿托伐他汀抑制高糖诱导PAI-1表达的效应可能部分通过RhoA/ROCK-NF-κB旁路调控。辛伐他汀与阿托伐他汀对高糖诱导PAI-1表达的抑制程度无差异。代谢综合征病人可能因他汀的多向性作用而有更多获益。
Vascular diseases are the most serious complications of diabetes, most diabeticpatients died of cardiovascular and cerebrolvascular atherosclerosis and diabeticnephropathy. The risk of cardiovascular events is significantly higher in diabetic patients
with microvascular complications. Therefore, it’s extremely important to call for morefocus and studies on microvascular complications of type2diabetes to prevent majorvascular events and induce mortality. The abnormity of fibrinolytic system plays animportant role in diabetic complications. The most important fibrinolytic inhibitor isplasminogen activator (PAI-1) which is linked to the onset and development ofcardiovascular and cerebrolvascular diseases.
Statins has multifunctional benifits except lipid lowing such as fibrinolysis, improvingendothelial function and antithrombin effect, etc. Whether diabetic patients withmicrovascular complications could benefit more from statins treatment by improvingfibrinolysis and the mechanism of fibrinolytic effects of statins deserves further studies.That’s the main content of this study.
Objective The aim of our study was to compare the effect of simvastatin on reducingplasma plasminogen activator inhibitor-1levels in diabetic patients with or withoutmicrovascular complications.
Methods We enrolled129type2diabetic patients with (n=79) and without (n=50) diabetic microvascular complications and56control subjects. Plasma PAI-1levels weremeasured by ELISA before and after3months simvastatin treatment in18diabetic patientswith and17without microvascular complications. Common lipid and glucose metabolicparameters were also measured.
Results Diabetic patients have higher PAI-1lever compared with matched healthysubjects, and those with microvascular complications exhibited significantly higher levelsof PAI-1than those without. Plasma PAI-1levels were significantly reduced after3monthstreatment of simvastatin. The degree of reduction of PAI-1in group of microvascularcomplications was greater than that of group of diabetes without microvascularcomplications.
Conclusion Type2diabetes exhibited impaired fibrinolytic function, and more severeimpairment observed in group with microvascular complications. Therapy with simvastatinimproved fibrinolytic function，thus diabetic patients with microvascular complicationsbenefit more compared with those without microvascular complications.
Objective This study was to compare two methods of isolating adult rat cardiacmicrovascular endothelial cells (CMEC) and improve the methods.
Methods We use tissue adhere method and enzyme digestion procedure respectivelyto isolate CMEC. Immunofluorescence assay was used to identify specific expression ofCD31on the surface of CMEC.
Results We isolated CMEC successfully by these two different methods. The positiverates of CD31were no less than95%. The method of enzyme digestion not only has theadvantage of shorter time to gain a certain amount of cells, it is also a stable procedure toget relatively higher purity of cells compared to tissue adhere method.
Conclusion We recommend using the method of enzyme digestion to obtain highpurity CMEC in good condition.
Objective The aim of this study was to investigate the possible proinflammatorysignaling pathways involved in statin inhibition of glucose-induced plasminogen activatorinhibitor-1(PAI-1) expression in cardiac microvascular endothelial cells (CMECs).
Methods Primary rat CMECs were grown in the presence of5.7mmol/L or23mmol/L glucose. PAI-1mRNA and protein expression levels were measured by real-timePCR and ELISA, respectively. A pull-down assay was performed to determine RhoAactivity. IκBα protein expression was measured by western blotting, and NF-κBtranscription activity was determined by a dual luciferase reporter gene assay.
Results PAI-1mRNA and protein expression levels were both increased with highglucose concentrations, but they were significantly suppressed by simvastatin andatorvastatin treatment (P<0.01) and the effects were reversed by mevalonate (MVA,100μM) and geranylgeranyl pyrophosphate (GGPP,10μM) but not farnesyl pyrophosphate(FPP,10μM). Such effects were similar to those of a RhoA inhibitor, C3exoenzyme (5μg/mL), inhibitors of RhoA kinase (ROCK), Y-27632(10μmol/L) and hydroxyfasudil (10μmol/L), and a NF-κB inhibitor, BAY11-7082(5μmol/L). High glucose-induced RhoAand NF-κB activations in CMECs were both significantly inhibited by statins (P<0.01).Simvastatin and atorvastatin equally suppress high glucose-induced PAI-1expression.
Conclusion These effects of statins may occur partly by regulating theRhoA/ROCK-NF-κB pathway. The multifunctional roles of statins may be particularlybeneficial for patients with metabolic syndrome.
引文
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3. Festa A, Williams K, Tracy RP, et al. Progression of plasminogen activator inhibitor-1and fibrinogen levels in relation to incident type2diabetes. Circulation.2006;11,113(14):1753–1759.
4. de Vries FM, Denig P, Pouwels KB, et al. Primary prevention of major cardiovascularand cerebrovascular events with statins in diabetic patients: a meta-analysis. Drugs.2012,24;72(18):2365-73.
5. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention ofcardiovascular disease with atorvastatin in type2diabetes in the CollaborativeAtorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlledtrial. Lancet.2004,21-27;364(9435):685-96.
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