反义纤溶酶原激活物抑制剂1 RNA对家兔动脉粥样硬化形成的影响

为探讨纤溶酶原激活物抑制剂1反义RNA对家兔血浆纤溶活性及纤溶酶原激活物抑制剂1的表达、血脂及对动脉粥样硬化斑块形成的影响,通过聚合酶链反应扩增纤溶酶原激活物抑制剂1第二外显子,将聚合酶链反应产物纯化克隆后连入真核细胞表达载体pcDNA3.1,构建纤溶酶原激活物抑制剂1 反义RNA重组质粒.将pcDNA3.1-反义纤溶酶原激活物抑制剂1重组质粒注射到哈尔滨大白兔腹部皮下组织.通过发色底物法测定家兔血浆组织型纤溶酶原激活物及纤溶酶原激活物抑制剂1活性变化,通过免疫组织化学方法检测组织中纤溶酶原激活物抑制剂1表达的改变.测定家兔血脂变化,病理检测其动脉粥样硬化程度.结果显示,应用反义纤溶酶原激活物抑制剂1 RNA重组质粒的家兔血浆纤溶酶原激活物抑制剂1活性降低,组织型纤溶酶原激活物活性升高, 纤溶酶原激活物抑制剂1蛋白表达于内皮细胞,而在平滑肌细胞中未表达 (动脉粥样硬化对照组中内皮细胞、平滑肌细胞和泡沫细胞内均有表达);应用反义纤溶酶原激活物抑制剂1 RNA重组质粒的家兔胆固醇和甘油三酯明显低于动脉粥样硬化对照组(96±42 mg/L比123±12 mg/L, 15±10 mg/L比46±29 mg/L),且动脉粥样硬化程度亦轻于后者.以上提示,反义纤溶酶原激活物抑制剂1 RNA重组质粒的皮下注射能有效阻断家兔体内纤溶酶原激活物抑制剂1蛋白的合成,减轻动脉粥样硬化程度.     

缺血性心脑血管疾病患者血浆纤溶酶原激活物及纤溶酶原激活物抑制剂1的测定及临床意义

目的研究缺血性心脑血管疾病患者血浆尿激酶型纤溶酶原激活物及其受体、组织型纤溶酶原激活物及其抑制剂1的水平及意义。方法应用酶联免疫吸附试验测定急性脑梗死、急性心肌梗死及不稳定型心绞痛患者血浆尿激酶型纤溶酶原激活物及其受体、组织型纤溶酶原激活物及其抑制剂1的水平。结果(1)脑梗死患者急性期血浆尿激酶型纤溶酶原激活物轻度升高(P>0.05),恢复期明显回落(P<0.05),尿激酶型纤溶酶原激活物受体水平在急性期明显升高(P<0.01),恢复期进一步升高;血浆中组织型纤溶酶原激活物含量在急性期明显低于对照组(P<0.01),而纤溶酶原激活物抑制剂1含量则明显高于对照组(P<0.01),恢复期纤溶酶原激活物抑制剂1水平趋于正常,而血浆中组织型纤溶酶原激活物水平与对照组比较仍存在一定差异(P<0.05)。(2)急性心肌梗塞患者血浆尿激酶型纤溶酶原激活物受体水平急性期明显升高(P<0.05),恢复期进一步升高(P<0.01),尿激酶型纤溶酶原激活物水平均大致正常;急性期血浆中血浆中组织型纤溶酶原激活物及纤溶酶原激活物抑制剂1含量均明显高于对照组(P<0.01),恢复期明显回落,纤溶酶原激活物抑制剂1趋于正常,血浆中组织型纤溶酶原激活物水平仍高于对照组(P<0.05)。(3)不稳定型心绞痛患者急性期(入院时)血浆尿激酶型纤溶酶原激活物受体水平明显升高(P<0.01),恢复期(入院后二周)回落,但仍明显高于对照组(P<0.05),尿激酶型纤溶酶原激活物水平与对照组比较均未见明显差异(P>0.05);急性期血浆中组织型纤溶酶原激活物含量明显低于正常组(P<0.01),而纤溶酶原激活物抑制剂1含量略高于对照组(P>0.05),恢复期两者含量均趋于正常(P>0.05)。结论缺血性心脑血管疾病患者存在不同程度的凝血纤溶系统失平衡,对疾病的发生发展起重要作用。     

纤溶酶原激活物抑制物-1在肺血栓栓塞症、肺纤维化、支气管哮喘中的作用研究进展

纤溶酶原激活物抑制物-1是丝氨酸蛋白酶抑制剂家族成员之一,是纤溶酶原激活物快速、专一、有效的生理抑制剂,可影响由组织型纤溶酶原激活物参与的纤溶过程,以及尿激酶型纤溶酶原激活物参与的生理病理条件下纤维蛋白溶解、细胞外基质循环、细胞迁移、组织修复、肿瘤浸润及转移等过程.     

肿瘤坏死因子α对人脐静脉内皮细胞纤溶酶原激活物抑制剂1表达及转录调控的影响

探讨肿瘤坏死因子α对人脐静脉内皮细胞纤溶酶原激活物抑制剂1活性和mRNA表达的影响，以及纤溶酶原激活物抑制剂1基因5’上游序列的调控元件在该基因转录调控中的作用。体外培养人脐静脉内皮细胞，加入不同浓度肿瘤坏死因子α作用不同时间。采用发色底物法测定纤溶酶原激活物抑制剂1活性。Northern印迹分析法测定纤溶酶原激活物抑制剂1 mRNA水平。基因重组技术构建四个含人纤溶酶原激活物抑制剂1基因不同长度5’上游序列的荧光素酶报告基因质粒，瞬时转染进入内皮细胞，并测定荧光素酶的表达情况。运用聚合酶链反应和序列分析法对构建质粒上的三个AP-元件分别进行定点突变。结果发现，不同浓度肿瘤坏死因子α作用人脐静脉内皮细胞后，纤溶酶原激活物抑制剂1活性和mRNA表达量均明显增高；当转染质粒含有纤溶酶原激活物抑制剂1基因上游序列-1509/ 90和-823／ 90时，肿瘤坏死因子α使转染细胞的荧光素酶表达量比对照组明显增高；当转染质粒含有-553／ 90和-47， 90时，肿瘤坏死因子α的诱导作用不明显。在纤溶酶原激活物抑制剂15’上游序列的三个AP-1元件突变后，肿瘤坏死因子α的诱导作用明显降低。结果提示，肿瘤坏死因子α增强血管内皮细胞纤溶酶原激活物抑制剂1活性与mRNA表达；纤溶酶原激活物抑制剂1活性提高与其mRNA表达增加呈正相关；纤溶酶原激活物抑制剂15’上游序列中三个AP-1元件在肿瘤坏死因子α对纤溶酶原激活物抑制剂1诱导中具有重要调控作用。     

川芎嗪抗血栓形成的机制研究

纤溶酶原激活物抑制剂-1是一种重要的促凝血因子。内毒素脂多糖通过刺激血管内皮细胞分泌纤溶酶原激活物抑制剂-1导致炎症过程中血栓形成。为探讨其机制，本文采用酶联免疫吸附试验法、North-ern印迹法和电泳迁移法观察中药川芎嗪对内毒素脂多糖所致内皮细胞纤溶酶原激活物抑制剂-1表达的影响及可能机制进行探讨。结果发现．川芎嗪不仅抑制内毒素脂多糖所致内皮细胞纤溶酶原激活物抑制剂-1蛋白分泌和mRNA表达．而且抑制内皮细胞纤溶酶原激活物抑制剂-1基础水平的表达。此结果提示，川芎嗪并非通过核因子NF－KB途径抑制内毒素脂多糖所致内皮细胞纤溶酶原激活物抑制剂-1表达增强的作用。     

氯沙坦和依那普利对左旋硝基精氨酸诱导的高血压大鼠纤溶功能的影响

为探讨肾素-血管紧张素系统在纤溶功能紊乱中的意义;用腹腔注射左旋硝基精氨酸诱导大鼠高血压,导致纤溶功能紊乱,从第2周开始分别给血管紧张素Ⅱ的1型受体阻滞剂氯沙坦和血管紧张素转换酶抑制剂依那普利干预,于第5周末应用发色底物法测定各组大鼠组织型纤溶酶原激活物及其抑制剂-1 的血浆活性,并观察氯沙坦和依那普利干预的影响.结果发现,与对照组相比,高血压大鼠血浆纤溶酶原激活物抑制剂-1活性增强50%,组织型纤溶酶原激活物活性减低34%,纤溶酶原激活物抑制剂-1与组织型纤溶酶原激活物的比值升高127%,差异均有显著性 (P<0.01).氯沙坦或依那普利干预均可使上述指标得到显著改善 (P<0.01).离体血管孵育时高血压大鼠血管释放纤溶酶原激活物抑制剂-1的能力比对照组明显增强 (P<0.01);氯沙坦或依那普利干预使其生成纤溶酶原激活物抑制剂-1的基础水平及不同浓度凝血酶诱导的过度释放分别减少19%～46%和25%～50% (P<0.01),两种干预间差异无显著性;给10.0 kIU/L凝血酶刺激时,高血压大鼠离体血管组织型纤溶酶原激活物的生成较对照组下降32% (P<0.05),氯沙坦和依那普利干预均未能改善这种下降趋势.结果表明,氯沙坦或依那普利干预可抑制高血压大鼠血管纤溶酶原激活物抑制剂-1的过度生成,但对组织型纤溶酶原激活物无影响.提示肾素-血管紧张素系统对纤溶系统的调节主要是通过调节纤溶酶原激活物抑制剂-1的生成,并经血管紧张素Ⅱ介导.     

冠心病患者血清甘油三酯水平与纤溶激活系统的关系

为研究冠心病患者血清甘油三酯水平与纤溶激活系统的关系,比较分析冠心病患者、高甘油三酯血症患者及正常对照者的血清甘油三酯水平、组织型纤溶酶原激活物及其抑制剂活性。纤溶酶原激活物抑制剂1、组织型纤溶酶原激活物活性测定采用发色低物法,血清甘油三酯浓度测定采用酶法。结果表明,高甘油三酯血症患者及冠心病患者纤溶酶原激活物抑制剂1活性较正常人升高,组织型纤溶酶原激活物活性较正常人下降。冠心病患者及高甘油三酯血症患者均有不同程度的纤溶活性下降,以急性心肌梗死、不稳定型心绞痛伴高甘油三酯组改变尤为明显。血清甘油三酯水平与血浆组织型纤溶酶原激活物活性呈负相关,与纤溶酶原激活物抑制剂1活性呈正相关。结果提示,甘油三酯通过影响纤溶功能参与冠心病的形成与发展。     

纤维蛋白原、纤维蛋白及其降解产物对共培养血管内皮细胞纤溶活性的影响

目的研究纤维蛋白原（Fg）、纤维蛋白（Fb）及其降解产物（FDP）对共培养体系中人脐静脉内皮细胞组织型纤溶酶原激活物和纤溶酶原激活物抑制剂表达的影响。方法应用Transwell膜建立人脐静脉内皮细胞-兔主动脉平滑肌细胞共培养体系，在不同浓度（0、0．5、1．5、3．0、4．5和6．0g／L）Fg、Fb和FDP干预24h后，分别检测该共培养体系中人脐静脉内皮细胞组织型纤溶酶原激活物和纤溶酶原激活物抑制剂mRNA水平（RT-PCR法）以及培养上清中组织型纤溶酶原激活物和纤溶酶原激活物抑制剂抗原含量（ELISA法）与活性（发色底物法）的变化情况。结果Fg对组织型纤溶酶原激活物的表达没有显著影响，较高浓度的Fg（3．0～4．5g／L）可明显促进纤溶酶原激活物抑制剂mRNA表达、抗原含量及活性升高，但过高浓度的Fg（6．0g／L）却抑制纤溶酶原激活物抑制剂的表达。3．0-4．5g／L的Fb对组织型纤溶酶原激活物mRNA和抗原含量都起上调作用，同时显著下调组织型纤溶酶原激活物活性。较高浓度的Fb（1．5-4．5g／L）则可明显上调纤溶酶原激活物抑制剂的表达，且在mRNA、蛋白和活性水平趋势基本一致。3．0-6．0g／L的FDP均可明显下调组织型纤溶酶原激活物mRNA、蛋白和活性水平，1．5-6．0mg／ml的FDP均可促进纤溶酶原激活物抑制剂的高表达。结论Fg、Fb和FDP可以通过影响组织型纤溶酶原激活物和纤溶酶原激活物抑制剂的表达，引起纤溶活性降低，参与动脉粥样硬化的发展进程。     

纤溶酶原激活物抑制剂-1与心血管疾病

纤溶酶原激活物抑制剂-1是纤溶系统的主要调节因子,通过抑制纽织型纤溶酶原活化剂影响血浆纤溶和凝血系统的平衡,引起或者加速心血管疾病的发生发展。纤溶酶原激活物抑制剂-1对心血管疾病的诊断、预后,尤其对冠心病的诊断、分型、危险分层、预后及经皮冠状动脉介入治疗后的再狭窄的判断有重要指导意义。心血管疾病相关的的辅助检查中,纤溶酶原激活物抑制剂-1将提供一种新的选择。     

山莨菪碱下行调节培养的内皮细胞表达纤溶酶原激活物抑制剂1

为了探讨山莨菪碱对正常及内毒素脂多糖刺激过的内皮细胞纤溶酶原激活物抑制剂 1表达的作用及机制。本文采用酶消化法培养人脐静脉内皮细胞 ;用酶联免疫吸附试验 (ELISA)方法检测人脐静脉内皮细胞条件培养基纤溶酶原激活物抑制剂 1和组织型纤溶酶原激活物蛋白量 ;用Northern印迹方法检测人脐静脉内皮细胞纤溶酶原激活物抑制剂 1的mRNA表达 ;用电泳迁移检测法对人脐静脉内皮细胞的核因子κB核内转移情况进行研究。结果发现 ,脂多糖能使人脐静脉内皮细胞纤溶酶原激活物抑制剂 1蛋白及mRNA表达显著增强 ,但加入山莨菪碱后 ,脂多糖的这种作用明显减弱。而且 ,山莨菪碱还能抑制人脐静脉内皮细胞纤溶酶原激活物抑制剂 1基础水平的表达。经脂多糖刺激的人脐静脉内皮细胞核提取物与核因子κB探针结合明显增强 ,而山莨菪碱则能阻止脂多糖致核因子κB的核内转移现象。提示山莨菪碱不仅下行调节脂多糖所致内皮细胞纤溶酶原激活物抑制剂 1的蛋白分泌和mRNA表达 ,而且下行调节其纤溶酶原激活物抑制剂 1基础水平表达 ,这种调节可能通过核因子κB途径而发挥作用     

The effect of plasminogen activator inhibitor-1 -675 4G/5G polymorphism on PAI-1 gene expression and adipocyte differentiation

Obesity is a complex, multifactorial chronic disease frequently associated with cardiovascular risks, hypertriglyceridemia, low high-density lipoprotein-cholesterol, high blood pressure, and the insulin resistance that appears to be central to the pathogenesis of Type II diabetes. Plasminogen activator inhibitor-1 expression induced in differentiating adipose tissue, but its role in adipogenesis and obesity is poorly understood. Circulating plasminogen activator inhibitor-1 levels are elevated at an early stage of impaired glucose tolerance, resulting in diabetes and metabolic syndrome. Plasminogen activator inhibitor-1 levels are also significantly elevated in the plasma of obese individuals and in adipose tissues of obese mice and humans. Some investigators proposed that the -675 4G/5G polymorphism in plasminogen activator inhibitor-1 promoter caused overexpression of this gene and predisposed carriers to obesity. In this study, we investigated the role of -675 4G/5G polymorphism in plasminogen activator inhibitor-1 promoter in the expression of this gene and the contribution of plasminogen activator inhibitor-1 to adipogenesis. Using a dual-luciferase promoter assay, we determined that the -675 4G/5G polymorphism contributes significantly to overexpression of plasminogen activator inhibitor-1 in the course of adipogenesis. The antidiabetic agents troglitazone and ciglitazone inhibited reporter gene expression driven by wild-type and -675 4G/5G mutant promoter, as well as the expression of endogenous plasminogen activator inhibitor-1, indicating that suppression of plasminogen activator inhibitor-1 expression may contribute to antidiabetic effects of these agents. The results indicate that absence of plasminogen activator inhibitor-1 in adipocytes may protect the cells against insulin resistance by promoting glucose uptake and adipocyte differentiation via a decrease in the peroxisome proliferator activated receptor-gamma expression that modulates the adipocyte differentiation.     

Characterization of signal transduction pathway in neurotropic action of angiotensin II in brain neurons.

Interaction of angiotensin II with the neuronal angiotensin type 1 receptor stimulates the PI3K signaling pathway. Our objective in this study was to investigate the hypothesis that the PI3K cascade regulates the neurotropic actions of angiotensin II in rat brain neurons. We followed growth associated protein-43 expression and neurite extension as markers of neurotropic activity. Angiotensin II, through its interaction with the angiotensin type 1 receptor, increased growth associated protein-43 expression and neurite extension. These effects were abolished by pretreatment of neurons with wortmannin and rapamycin, but not by PD 98059. Antisense oligonucleotides specific for p70(S6) kinase also inhibited angiotensin II-stimulated neurotropic activity. These data confirm the involvement of PI3K and p70(S6) kinase in angiotensin II-mediated neurotropic action. Further support for this was provided by the observation that angiotensin II caused a time-dependent stimulation of p70(S6) kinase by an angiotensin type 1 receptor-mediated process. We also found that the neurotropic actions of angiotensin II are mediated by plasminogen activator inhibitor-1. Evidence for this includes 1) angiotensin II-stimulated neuronal plasminogen activator inhibitor-1 gene expression, 2) potent neurotropic action of exogenous plasminogen activator inhibitor-1, and 3) inhibitory neurotropic effect of angiotensin II by antisense oligonucleotide-mediated depletion of plasminogen activator inhibitor-1. Finally, we found that the neurotropic action of plasminogen activator inhibitor-1 is not blocked by either angiotensin type 1 receptor antagonist or inhibitors of PI3K or p70(S6) kinase, indicating that the plasminogen activator inhibitor-1 step is downstream from the p70(S6) kinase. These observations demonstrate that angiotensin II is a neurotropic hormone that engages a distinct PI3K-p70(S6) kinase-plasminogen activator inhibitor-1 signaling pathway for this action.     

Effect of valsartan on angiotensin II-induced plasminogen activator inhibitor-1 biosynthesis in arterial smooth muscle cells

Previous studies have shown that angiotensin II stimulates the synthesis of plasminogen activator inhibitor-1 in cultured vascular cells, which suggests that activation of the renin-angiotensin system may impair fibrinolysis. We have investigated the effects of angiotensin II and of valsartan, a recently developed angiotensin II antagonist that is highly specific and selective for the angiotensin II subtype 1 receptor, on plasminogen activator inhibitor-1 secretion by smooth muscle cells isolated from rat and human vessels. Angiotensin II induced a time- and concentration-dependent increase of plasminogen activator inhibitor activity in supernatants of rat aortic cells, which reached a plateau after 6 hours of incubation with 100 nmol/L angiotensin II (2.4+/-0.6-fold over control value; P:<0.001). The angiotensin II-induced plasminogen activator inhibitor activity was inhibited, in a concentration-dependent manner, by valsartan with an IC(50) value of 21 nmol/L. Valsartan fully prevented the angiotensin II-induced increase in plasminogen activator inhibitor-1 protein and mRNA. Furthermore, angiotensin II doubled the secretion of plasminogen activator inhibitor-1 by smooth muscle cells obtained from human umbilical and internal mammary arteries, and valsartan fully prevented it. Angiotensin II did not affect the secretion of tissue plasminogen activator antigen by any of the cell systems tested. Thus, valsartan effectively inhibits angiotensin II-induced plasminogen activator inhibitor-1 secretion without affecting that of tissue plasminogen activator in arterial rat and human smooth muscle cells.     

Plasma plasminogen activator inhibitor-1 activity in normoglycemic hypertriglyceridemic north Asian Indian subjects: a preliminary case-control study.

BACKGROUND: Recent evidence suggests that increased activity of plasma plasminogen activator inhibitor-1, an important component of the insulin resistance syndrome, plays a crucial role in the pathogenesis of atherosclerosis. METHODS AND RESULTS: In this case-control study, relationships between plasma plasminogen activator inhibitor-1 activity, serum triglyceride levels and hyperinsulinemia were explored in 40 non-diabetic patients with primary hypertriglyceridemia (Group 1) and 40 non-diabetic normotriglyceridemic controls (Group 2) matched for potential confounders like smoking and physical activity. Mean values of fasting serum insulin levels were increased in Group 1 (p>0.05). Hyperinsulinemia was observed in 14 (17.5%) individuals in Group 1 and 11 (13.8%) individuals in Group 2. Mean plasma plasminogen activator inhibitor-I activity in Group 1 (9.8+/-8.4 IU) was higher than in Group 2 (7.0+/-7.7 IU), though the difference was not significant (p>0.05). However, when only subjects with elevated levels of plasma plasminogen activator inhibitor-1 activity were taken into account, mean values were significantly higher in Group 1 (p<0.05). The plasma plasminogen activator inhibitor-1 activity was higher in subjects with body mass index >25 in both the groups, significantly so in males (p=0.05). Hyperinsulinemic subjects with a body mass index >25 and raised serum triglyceride levels had higher mean values of plasma plasminogen activator inhibitor-1 activity (18.42+/-11.15 IU) than subjects with similar characteristics and normal triglyceride levels (14.22+/-8.20 IU, p<0.05). CONCLUSIONS: Though in the current study a trend for hyperinsulinemia and high plasma plasminogen activator inhibitor-1 activity was observed in hypertriglyceridemic subjects, a larger study is needed to achieve significant differences and correlations. Obese male subjects, irrespective of their lipid profile, are at risk for thrombotic events in view of their significantly higher plasma plasminogen activator inhibitor-1 values. Procoagulant tendency is further enhanced if hypertriglyceridemia and hyperinsulinemia are added on to obesity.     

Relationship between plasma plasminogen activator inhibitor-1 activity and VLDL triglyceride concentration,insulin levels and insulin sensitivity: studies in randomly selected normo- and hypertriglyceridaemic men

Summary Impaired fibrinolytic function secondary to elevated plasma plasminogen activator inhibitor-1 activity, hypertriglyceridaemia and hyperinsulinaemia are frequent findings in patients with coronary heart disease. It has been debated whether VLDL or insulin is the major regulator of plasma plasminogen activator inhibitor-1 activity. This study examines the relationships between plasma plasminogen activator inhibitor-1 activity and VLDL triglyceride concentration, fasting and post-oral glucose load insulin levels and insulin sensitivity, as estimated by the minimal model method. Subjects studied were randomly selected hypertriglyceridaemic (n=65) and age-matched normotriglyceridaemic (n=61) men, aged 40–50 years, recruited in a population survey. Plasma plasminogen activator inhibitor-1 activity was higher in the hypertriglyceridaemic than in the normotriglyceridaemic group (21±14 vs 10±8 mU/l; p<0.01). The hypertriglyceridaemic group had higher serum insulin, basal as well as 2 h after intake of the oral glucose load, and a lower insulin sensitivity index. In univariate analysis, plasma plasminogen activator inhibitor-1 activity correlated positively with VLDL triglycerides in both the hyper- and normotriglyceridaemic groups (r=0.43 r=0.60, respectively) and negatively with the insulin sensitivity index (r=–0.35 r=–0.44, respectively). In multivariate analysis, VLDL triglyceride levels were found to be independently related to plasma plasminogen activator inhibitor-1 activity in both groups, whereas insulin sensitivity/serum insulin levels were not. An unexpected finding was that the serum activity of the enzyme gamma glutamyl transpeptidase appeared to influence the relationships for plasma plasminogen activator inhibitor-1 in the hypertriglyceridaemic group. In conclusion, this population-based study indicates that VLDL triglyceride concentration is one of the major determinants of plasma plasminogen activator inhibitor-1 activity in both normotriglyceridaemic and hypertriglyceridaemic men.     

Type 2 diabetes: assessment of endothelial lesion and fibrinolytic system markers.

This study aimed to investigate whether endothelial cells are damaged and to evaluate fibrinolytic system function in patients with type 2 diabetes. For this proposal, plasma levels of von Willebrand factor (an endothelial marker of injury), homocysteine (an inductor of endothelial injury), D-dimer (a marker of coagulation cascade activation) and plasminogen activator inhibitor-1 (a fibrinolysis marker) were measured in individuals with both type 2 diabetes and high blood pressure, with type 2 diabetes, with high blood pressure and in healthy control individuals. No significant differences among groups were observed for von Willebrand factor and homocysteine plasma levels. The type 2 diabetes and high blood pressure group presented a significant difference to the other groups for D-dimer and also presented high values for plasminogen activator inhibitor-1. The high blood pressure group and type 2 diabetes group presented separately higher values of plasminogen activator inhibitor-1 compared with the control group. High levels of D-dimer and plasminogen activator inhibitor-1 in patients with type 2 diabetes and high blood pressure with normoalbuminuria therefore indicate a state of hypercoagulability and hypofibrinolysis, despite no evident microvascular injury supported by normal levels of von Willebrand factor and homocysteine.     

Clinical and biochemical predictors affect the choice and the short-term outcomes of different thrombolytic agents in acute myocardial infarction

BACKGROUND: The presence of plasminogen activator inhibitor-1, angiotensin-converting enzyme and others may play a role in unsuccessful recanalization after thrombolytic therapy. OBJECTIVES: To find out the clinical and biochemical predictors that may affect the choice and short-term outcomes following different thrombolytic agents in acute myocardial infarction. METHODOLOGY: Angiotensin-converting enzyme and plasminogen activator inhibitor-1 plasma levels of 184 patients with acute myocardial infarction, treated with streptokinase, metalyze or reteplase, were determined. Failure of thrombolysis was assessed by noninvasive reperfusion criteria. Prolonged hospitalization, impaired left ventricular ejection fraction and reinfarction were considered as short-term outcomes. RESULTS: Patients who received streptokinase developed higher incidence of >50% resolution of ST-segment elevation (82.5 vs. 64.7%, P-value<0.05, in comparison with metalyze and 82.5 vs. 55.7%, P-value 0.001, in comparison with reteplase) than those who received other thrombolytic agents. High plasma angiotensin-converting enzyme was associated with prolonged hospitalization (55, 63 and 94%, P<0.02) following streptokinase, metalyze and reteplase, respectively. High plasma plasminogen activator inhibitor-1 is associated with impaired left ventricular ejection fraction (55.3, 76.7 and 68.5%, P<0.09), ST resolution<50% (13.2, 36.7 and 37.5%, P=0.03), ST resolution>50% (86.8, 63.3 and 62.5%, P=0.03) following streptokinase, metalyze and reteplase, respectively. CONCLUSIONS: Rapid determination of pretreatment angiotensin-converting enzyme and plasminogen activator inhibitor-1 plasma levels in patients with acute myocardial infarction may influence the choice and outcomes of the thrombolytic agents. The presence of a high plasma level of either angiotensin-converting enzyme or plasminogen activator inhibitor-1 is significantly associated with adverse short-term outcomes after treatment with reteplase or metalyze.     

The Changes of Vasoactive Substances Originated Endothelium in Patients with Unstable Angina Pectoris Treated by Improved Thrombolytic Therapy

Objectives To analyze the changes of vasoactive substances originated from endothelium in patients with unstable angina pectoris treated by modified thrombolytic therapy and explore the mechanisms of the drug to treat unstable angina pectoris.Methods 120 patients with unstable angina pectoris who were not well responsed to common medication were studied. Their ECG stress tests were abnormal and there were ischemic changes in Holter. Urokinase 300,000 U was added in 100 ml normal saline and injected within 30 min once a day for 3 days. 300 mg aspirin was administrated a day before and during urokinase applications. Before and after urokinase treatments, endothelin-1, plasma tissue plasminogen activator and its inhibitor-1were determined. Results Compared with pretreatments, after treatments, the activities of tissue plasminogen activator increased, endothelin-1 and the inhibitor-1 decreased. The changes were significant. Conclusions Modified thrombolytic therapy can regulate the vasoactive substances originated endothelium in patients with unstable angina pectoris . The major substances include endothelin-1 ,plasma tissue plasminogen activator and inhibitor-1. This mechanism may suggest that urokinase can treat coronary heart disease effectively.     

Promoter (4G/5G) plasminogen activator inhibitor-1 genotype in Pima Indians: relationship to plasminogen activator inhibitor-1 levels and features of the insulin resistance syndrome

Summary Elevated plasminogen activator inhibitor-1 may contribute to vascular disease in diabetes mellitus. Pima Indians have a low incidence of cardiovascular disease despite having a high prevalence of non-insulin-dependent diabetes mellitus (NIDDM) which in this population is not associated with elevated plasminogen activator inhibitor-1 activity. In Caucasians an insertion/deletion (4G/5G) polymorphism in the promoter region of the plasminogen activator inhibitor-1 gene that has been related to activity levels of its protein in plasma differentially binds repressor and enhancer elements. In 265 Pima Indians (133 diabetic, 132 non-diabetic, 129 male, 136 female, mean age 46.6, range 34–68 years) the promoter genotype frequencies were 23.0 % for 4G/4G, 49.8 % for 4G/5G and 27.2 % for 5G/5G compared to 35.4 %, 50.8 % and 13.8 % respectively (χ² = 15.3, 2 df, p < 0.0005) previously reported in Caucasians with NIDDM. The mean plasma activity levels in the three genotypes in the Pima Indians were 18.2, 19.1 and 18.1 U/ml, respectively. Plasminogen activator inhibitor-1 activities correlated with plasma insulin (r = 0.38, p < 0.0001), body mass index (r = 0.24, p < 0.0001), and with triglyceride level (r = 0.12, p = 0.054) but there was no relationship between promoter genotype and activity. A steeper regression slope between plasminogen activator inhibitor-1 activity and triglycerides has been observed in Caucasians with the 4G/4G genotype as compared to Caucasians with the other genotypes. This was not found in the Pima population which may indicate a functional difference in this gene associated with reduced cardiovascular risk and may be involved in the lack of association of plasminogen activator inhibitor-1 levels with NIDDM in Pima Indians. [Diabetologia (1996) 39: 1512–1518] Received: 7 May 1996 and in revised form: 21 August 1996     

Increased global fibrinolytic capacity as a clue for activated fibrinolysis in pre-eclampsia.

The aim of this study was to compare fibrinolysis in normal pregnancy and pre-eclampsia using individual markers of thrombosis and fibrinolysis with the contribution of a new parameter, global fibrinolytic capacity. Coagulation was determined with thrombin-antithrombin complex and prothrombin fragment 1+2 (F 1+2) and fibrinolysis markers. Tissue plasminogen activator, plasminogen activator inhibitor-1 and global fibrinolytic capacity were determined in 14 normal pregnancies and 29 women with pre-eclampsia. global fibrinolytic capacity was also determined in 14 age-matched healthy women. The Mann-Whitney U test and Pearson correlation test were used for statistical analysis. Thrombin-antithrombin complex, prothrombin fragment 1+2 levels, and global fibrinolytic capacity levels in pre-eclamptic women were significantly higher than in women with normal pregnancies (P < 0.05). Tissue plasminogen activator, plasminogen activator inhibitor-1 levels were also significantly higher in the pre-eclampsia group (P < 0.001 and P < 0.05 respectively). No significant correlation was found between global fibrinolytic capacity and thrombin-antithrombin complex, prothrombin fragment 1+2 levels, tissue plasminogen activator or plasminogen activator inhibitor-1 activity. Our results suggest that both thrombin formation and fibrinolysis are increased in pre-eclampsia compared with normal pregnancy. The increased global fibrinolytic capacity indicates that fibrinolysis remains preserved in pre-eclampsia. We suggest that global fibrinolytic capacity may be a useful parameter for accurately measuring in-vivo fibrinolysis globally, instead of with single parameters which may overlook the complex interactions between coagulation and fibrinolytic systems.