Urokinase-type Plasminogen Activator Receptor (uPAR) Ligation Induces a Raft-localized Integrin Signaling Switch That Mediates the Hypermotile Phenotype of Fibrotic Fibroblasts

The urokinase-type plasminogen activator receptor (uPAR) is a glycosylphosphatidylinositol-linked membrane protein with no cytosolic domain that localizes to lipid raft microdomains. Our laboratory and others have documented that lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) exhibit a hypermotile phenotype. This study was undertaken to elucidate the molecular mechanism whereby uPAR ligation with its cognate ligand, urokinase, induces a motile phenotype in human lung fibroblasts. We found that uPAR ligation with the urokinase receptor binding domain (amino-terminal fragment) leads to enhanced migration of fibroblasts on fibronectin in a protease-independent, lipid raft-dependent manner. Ligation of uPAR with the amino-terminal fragment recruited α5β1 integrin and the acylated form of the Src family kinase, Fyn, to lipid rafts. The biological consequences of this translocation were an increase in fibroblast motility and a switch of the integrin-initiated signal pathway for migration away from the lipid raft-independent focal adhesion kinase pathway and toward a lipid raft-dependent caveolin-Fyn-Shc pathway. Furthermore, an integrin homologous peptide as well as an antibody that competes with β1 for uPAR binding have the ability to block this effect. In addition, its relative insensitivity to cholesterol depletion suggests that the interactions of α5β1 integrin and uPAR drive the translocation of α5β1 integrin-acylated Fyn signaling complexes into lipid rafts upon uPAR ligation through protein-protein interactions. This signal switch is a novel pathway leading to the hypermotile phenotype of IPF patient-derived fibroblasts, seen with uPAR ligation. This uPAR dependent, fibrotic matrix-selective, and profibrotic fibroblast phenotype may be amenable to targeted therapeutics designed to ameliorate IPF.     

Characterization of a Novel Class of Polyphenolic Inhibitors of Plasminogen Activator Inhibitor-1

Plasminogen activator inhibitor type 1, (PAI-1) the primary inhibitor of the tissue-type (tPA) and urokinase-type (uPA) plasminogen activators, has been implicated in a wide range of pathological processes, making it an attractive target for pharmacologic inhibition. Currently available small-molecule inhibitors of PAI-1 bind with relatively low affinity and do not inactivate PAI-1 in the presence of its cofactor, vitronectin. To search for novel PAI-1 inhibitors with improved potencies and new mechanisms of action, we screened a library selected to provide a range of biological activities and structural diversity. Five potential PAI-1 inhibitors were identified, and all were polyphenolic compounds including two related, naturally occurring plant polyphenols that were structurally similar to compounds previously shown to provide cardiovascular benefit in vivo. Unique second generation compounds were synthesized and characterized, and several showed IC₅₀ values for PAI-1 between 10 and 200 nm. This represents an enhanced potency of 10–1000-fold over previously reported PAI-1 inactivators. Inhibition of PAI-1 by these compounds was reversible, and their primary mechanism of action was to block the initial association of PAI-1 with a protease. Consistent with this mechanism and in contrast to previously described PAI-1 inactivators, these compounds inactivate PAI-1 in the presence of vitronectin. Two of the compounds showed efficacy in ex vivo plasma and one blocked PAI-1 activity in vivo in mice. These data describe a novel family of high affinity PAI-1-inactivating compounds with improved characteristics and in vivo efficacy, and suggest that the known cardiovascular benefits of dietary polyphenols may derive in part from their inactivation of PAI-1.     

Crystal Structure of the Michaelis Complex between Tissue-type Plasminogen Activator and Plasminogen Activators Inhibitor-1

Thrombosis is a leading cause of death worldwide. Recombinant tissue-type plasminogen activator (tPA) is the Food and Drug Administration-approved thrombolytic drug. tPA is rapidly inactivated by endogenous plasminogen activator inhibitor-1 (PAI-1). Engineering on tPA to reduce its inhibition by PAI-1 without compromising its thrombolytic effect is a continuous effort. Precise details, with atomic resolution, of the molecular interactions between tPA and PAI-1 remain unknown despite previous extensive studies. Here, we report the crystal structure of the tPA·PAI-1 Michaelis complex, which shows significant differences from the structure of its urokinase-type plasminogen activator analogue, the uPA·PAI-1 Michaelis complex. The PAI-1 reactive center loop adopts a unique kinked conformation. The structure provides detailed interactions between tPA 37- and 60-loops with PAI-1. On the tPA side, the S2 and S1β pockets open up to accommodate PAI-1. This study provides structural basis to understand the specificity of PAI-1 and to design newer generation of thrombolytic agents with reduced PAI-1 inactivation.     

PAI-1基因4G/5G多态性与中国地区原因不明习惯性流产的Meta分析

目的:探讨PAI-A基因4G/5G多态性跟中国地区原因不明习惯性流产的关系.方法:采用Stata10.0对所有纳入结果进行异质性检验,敏感分析,影响分析和发表偏移检验.结果:6篇文章共540名病例和672名对照纳入研究.敏感性分析之后,4G/5G多态性跟习惯性流产明显相关(显性模型OR=1.934,95％CI=1.355-2.760,隐性模型OR=1.657,95％CI=1.142-2.405),共显性模型OR=1.604,95％CI=1.309-1.965).结论:PAI-1基因4G/5G可能与中国地区原因不明习惯性流产有关.但仍然需要更多的实验证实.     

靶向纤溶酶原激活物抑制剂1的肿瘤治疗研究进展

肿瘤是严重危害人类健康的疾病.研究表明,实体瘤周围环境中的胞外基质蛋白、浸润性免疫细胞和间充质细胞分泌的蛋白质组等均与肿瘤的发生、发展以及肿瘤治疗的耐受性等密切相关.肿瘤微环境中一个重要调控因子,纤溶酶原激活物抑制剂1 (plasminogen activator inhibitor-1,PAI-1),不仅与组织型纤溶酶原激活物(tissue-type plasminogen activators,tPA)构成调节纤溶活性的一对关键物质,而且参与肿瘤的侵袭、浸润和转移等多个环节并扮演重要角色.本文针对近年来PAI-1的结构和功能方面研究新进展及其与肿瘤微环境的相关性进行综述,并提出PAI-1可作为抗肿瘤治疗的重要靶点.同时,本文也分析了PAI-1抑制剂对肿瘤干预的研究现状,指出PAI-1抑制剂对肿瘤治疗的潜在应用价值.     

Plasminogen Activator Inhibitor-1 (PAI-1) gene 4G/5G alleles frequency distribution in the Lebanese population

Plasminogen activator inhibitor-1 (PAI-1) is an inhibitor of fibrinolysis. Increased plasma PAI-1 levels play an essential role in the pathogenesis of cardiovascular risk and other diseases associated with thrombosis. The 4G/5G polymorphism of the PAI-1 promoter region has been extensively studied in different populations. We studied 160 healthy unrelated Lebanese individuals using a reverse hybridization PCR assay to detect the 5G/5G, 4G/5G and, 4G/4G genotypes of the PAI-1 gene and the frequencies of the 4G and 5G alleles. We found that 4G/5G genotype was the most prevalent (45.6%) followed by 5G/5G (36.9%) and 4G/4G (17.5%). The frequencies of the 4G and 5G alleles were calculated to be 0.403 and 0.597, respectively. Compared to other ethnic communities, the Lebanese population was found to harbour a relatively high prevalence of the rare 4G allele. This, in turn, may predispose this population to develop cardiovascular diseases and other thrombotic clinical conditions. This study aids to enhance our understanding of the genetic features of the Lebanese population.     

Myocardial Infarction Occurs with a Similar 24 h Pattern in the 4G/5G Versions of Plasminogen Activator Inhibitor-1

PAI-1 expression is regulated by a 4G/5G promoter polymorphism. The 4G allele is associated with greater circadian variation of PAI-1 levels. We hypothesized that the 24 h variation of cardiac risk is more pronounced among persons with the 4G4G genotype than among ones with 4G5G and 5G5G genotypes. We assessed the time of onset of symptoms in 623 consecutive patients with acute myocardial infarction (AMI) enrolled in the MISSION! Study between February 1, 2004, and October 29, 2006. All of the patients were genotyped for the PAI-1 4G/5G polymorphism. We quantified the amplitude of the 24 h variation of AMI with a generalized linear model with Poisson distribution. A morning peak, between 06:00–11:59 h (n?=?197; 32% of all cases), in the onset of symptoms of AMI was observed. The group composed of patients with the 4G4G genotype did not have a more pronounced morning peak than the groups composed of other genotypes; the 24 h variation was 38% (95% confidence interval 12–70%) in the group of 4G4G patients and 34% (14–58%) and 56% (20–100%) in the 4G5G and 5G5G groups of patients, respectively. Our findings show that 24 h variation of cardiac risk is not more pronounced among the 4G4G genotype of PAI-1. (Author correspondence: j.g.vanderbom@lumc.nl)     

糖尿病肾脏病与血纤溶酶原激活物抑制剂-1的相互影响

目的：观察糖尿痛肾脏病进展过程中血纤溶酶原激活物抑制剂-1的水平变化及应用药物干预其变化后产生的对糖尿病肾脏病的影响。方法：选择于聊城市人民医院就诊的糖尿病肾脏病患者88例,DKDⅢ期43例,DKDⅣ期45例。分别检测各期患者血PAI-1水平,观察其变化趋势。针对DKDⅢ期患者分为对照组（DKDⅢ-C组）和观察组（DKDⅢ-O组）,对照组给予常规降糖、保护肾脏及血管紧张素转化酶抑制剂等药物治疗。观察组在对照组治疗的基础上给予尿激酶5万U加入100ml生理盐水静脉滴注,每天1次。共14d。比较两组治疗前后血PAI-1水平、24h尿白蛋白量、血肌酐、空腹血糖和凝血酶原时间的变化。结果：DKDⅣ期患者血PAI-1水平明显高于DKDⅢ期患者（P〈0．001）。DKDⅢ-O组患者治疗后血PAI-1水平下降（P〈0．01）,且尿白蛋白减少程度有统计学意义（P〈0．01）,空腹血糖、血肌酐、凝血酶原时间影响无统计学差异（P〉0．05）。DKDⅢ-C组治疗前、后血PAI-1、24h尿白蛋白量、空腹血糖、血肌酐、凝血酶原时间变化均无统计学差异（P〉0．05）。结论：随糖尿病肾脏病进展,血PAI-1水平呈上升趋势,应用药物降低其水平后可减少早期DKD患者尿白蛋白量,对保护肾功能、延缓肾脏病进展有积极意义。     

糖尿病肾脏病与血纤溶酶原激活物抑制剂-1的相互影响

目的:观察糖尿病肾脏病进展过程中血纤溶酶原激活物抑制剂-1的水平变化及应用药物干预其变化后产生的对糖尿病肾脏病的影响。方法:选择于聊城市人民医院就诊的糖尿病肾脏病患者88例,DKDⅢ期43例,DKDⅣ期45例。分别检测各期患者血PAI-1水平,观察其变化趋势。针对DKDⅢ期患者分为对照组(DKDⅢ-C组)和观察组(DKDⅢ-O组),对照组给予常规降糖、保护肾脏及血管紧张素转化酶抑制剂等药物治疗。观察组在对照组治疗的基础上给予尿激酶5万U加入100ml生理盐水静脉滴注,每天1次,共14d。比较两组治疗前后血PAI-1水平、24 h尿白蛋白量、血肌酐、空腹血糖和凝血酶原时间的变化。结果:DKDⅣ期患者血PAI-1水平明显高于DKDⅢ期患者(P<0.001)。DKDⅢ-O组患者治疗后血PAI-1水平下降(P<0.01),且尿白蛋白减少程度有统计学意义(P<0.01),空腹血糖、血肌酐、凝血酶原时间影响无统计学差异(P>0.05)。DKDⅢ-C组治疗前、后血PAI-1、24h尿白蛋白量、空腹血糖、血肌酐、凝血酶原时间变化均无统计学差异(P>0.05)。结论:随糖尿病肾脏病进展,血PAI-1水平呈上升趋势,应用药物降低其水平后可减少早期DKD患者尿白蛋白量,对保护肾功能、延缓肾脏病进展有积极意义。     

miR-30b,Down-Regulated in Gastric Cancer,Promotes Apoptosis and Suppresses Tumor Growth by Targeting Plasminogen Activator Inhibitor-1

Background

Gastric cancer is one of the most common malignant diseases worldwide. Emerging evidence has shown that microRNAs (miRNAs) are associated with tumor development and progression. Our previous studies have revealed that H. pylori infection was able to induce the altered expression of miR-30b in gastric epithelial cells. However, little is known about the potential role of miR-30b in gastric cancer.

Methods

We analyzed the expression of miR-30b in gastric cancer cell lines and human gastric cancer tissues. We examined the effect of miR-30b mimics on the apoptosis of gastric cancer cells in vitro by flow cytometry (FCM) and caspase-3/7 activity assays. Nude mouse xenograft model was used to determine whether miR-30b is involved in tumorigenesis of gastric cancer. The target of miR-30b was identified by bioinformatics analysis, luciferase assay and Western blot. Finally, we performed the correlation analysis between miR-30b and its target expression in gastric cancer.

Results

miR-30b was significantly down-regulated in gastric cancer cells and human gastric cancer tissues. Enforced expression of miR-30b promoted the apoptosis of gastric cancer cells in vitro, and miR-30b could significantly inhibit tumorigenicity of gastric cancer by increasing the apoptosis proportion of cancer cells in vivo. Moreover, plasminogen activator inhibitor-1 (PAI-1) was identified as the potential target of miR-30b, and miR-30b level was inversely correlated with PAI-1 expression in gastric cancer. In addition, silencing of PAI-1 was able to phenocopy the effect of miR-30b overexpression on apoptosis regulation of cancer cells, and overexpression of PAI-1 could suppressed the effect of promoting cell apoptosis by miR-30b, indicating PAI-1 is potentially involved in miR-30b-induced apoptosis on cancer cells.

Conclusion

miR-30b may function as a novel tumor suppressor gene in gastric cancer by targeting PAI-1 and regulating the apoptosis of cancer cells. miR-30b could serve as a potential biomarker and therapeutic target against gastric cancer.     

Plasminogen Activator Inhibitor-1 Expression by Brain Microvessel Endothelial Cells Is Inhibited by Elevated Glucose

Abstract: Patients with diabetes are predisposed to microvascular disease. In the retina and brain, this is characterized by neovascularization and new capillary formation. Because of the potential importance of plasmin generation in these processes, we evaluated the effect of elevated glucose concentrations on expression of plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), and urokinase (uPA) in cultured bovine brain endothelial cells (BBEC) versus cultured bovine aortic endothelial cells (BAEC). We observed that BBEC PAI-1 mRNA levels were decreased fivefold in cells cultured in media containing 20 m M glucose compared with BBEC cultured in media with 5.5 m M glucose, whereas expression of PAI-1 mRNA in BAEC, bovine mesenteric endothelial cells, and human umbilical vein endothelial cells was not modulated under these conditions. Expression of PAI-1 protein was also inhibited by growth of BBEC in elevated glucose, but the effect was less marked than at the mRNA level. Elevated glucose did not decrease expression of PAI-1 protein by BAEC. Withdrawal of acidic fibroblast growth factor enhanced expression of PAI-1 mRNA and protein in BBEC. Expression of tPA mRNA was not affected by the glucose concentration of the medium, and uPA mRNA was not detected in our BBEC cultures. A decrease in the local tissue activity of PAI-1 by elevated glucose concentrations, with no effect on tPA or uPA expression, would lead to an increase in the plasmin activity and thereby predispose neural tissues, such as the cerebrum and retina, of diabetic patients to neovascularization.     

Placenta Growth Factor (PlGF), a Novel Inducer of Plasminogen Activator Inhibitor-1 (PAI-1) in Sickle Cell Disease (SCD)

Sickle cell disease (SCD) is characterized by a prothrombotic state. Plasminogen activator inhibitor-1 (PAI-1) is known to modulate fibrinolysis, lung injury/fibrosis, and angiogenesis. However, its role in SCD is less understood, and the molecular mechanisms underlying increased PAI-1 are unknown. Herein, we show a novel link between PAI-1 and sickle erythropoiesis. Plasma PAI-1 levels were high in SCD patients at steady state and in two humanized sickle mouse models, with increased PAI-1 immunolabeling in sickle mouse lung, bronchial epithelial cells, alveolar macrophages, and pulmonary microvascular endothelial cells. Placenta growth factor (PlGF), released at high levels by sickle erythroblasts, induced PAI-1 expression in primary human pulmonary microvascular endothelial cells and monocytes through activation of c-Jun N-terminal kinase (JNK), NADPH oxidase, and hypoxia-inducible factor-1α (HIF-1α). Analysis of the human PAI-1 promoter revealed this induction was mediated by hypoxia-response element (HRE)-1, HRE-2, and distal activator protein (AP-1) sites. We also identify the involvement of c-Jun, c-Jun/c-Fos, and JunD, but not JunB, in binding with AP-1 sites of the PAI-1 promoter upon PlGF induction. Consistent with these findings, levels of PAI-1 were low in PlGF knock-out mice and sickle-PlGF knock-out mice; overexpression of PlGF in normal mice increased circulating PAI-1. In conclusion, we identify a novel mechanism of PAI-1 elevation in SCD.     

Measurement of the Pressure-volume Curve in Mouse Lungs

In recent decades the mouse has become the primary animal model of a variety of lung diseases. In models of emphysema or fibrosis, the essential phenotypic changes are best assessed by measurement of the changes in lung elasticity. To best understand specific mechanisms underlying such pathologies in mice, it is essential to make functional measurements that can reflect the developing pathology. Although there are many ways to measure elasticity, the classical method is that of the total lung pressure-volume (PV) curve done over the whole range of lung volumes. This measurement has been made on adult lungs from nearly all mammalian species dating back almost 100 years, and such PV curves also played a major role in the discovery and understanding of the function of pulmonary surfactant in fetal lung development. Unfortunately, such total PV curves have not been widely reported in the mouse, despite the fact that they can provide useful information on the macroscopic effects of structural changes in the lung. Although partial PV curves measuring just the changes in lung volume are sometimes reported, without a measure of absolute volume, the nonlinear nature of the total PV curve makes these partial ones very difficult to interpret. In the present study, we describe a standardized way to measure the total PV curve. We have then tested the ability of these curves to detect changes in mouse lung structure in two common lung pathologies, emphysema and fibrosis. Results showed significant changes in several variables consistent with expected structural changes with these pathologies. This measurement of the lung PV curve in mice thus provides a straightforward means to monitor the progression of the pathophysiologic changes over time and the potential effect of therapeutic procedures.     

Sphingosine 1-Phosphate (S1P) Receptor Agonists Mediate Pro-fibrotic Responses in Normal Human Lung Fibroblasts via S1P2 and S1P3 Receptors and Smad-independent Signaling

Synthetic sphingosine 1-phosphate receptor 1 modulators constitute a new class of drugs for the treatment of autoimmune diseases. Sphingosine 1-phosphate (S1P) signaling, however, is also involved in the development of fibrosis. Using normal human lung fibroblasts, we investigated the induction of fibrotic responses by the S1P receptor (S1PR) agonists S1P, FTY720-P, ponesimod, and SEW2871 and compared them with the responses induced by the known fibrotic mediator TGF-β1. In contrast to TGF-β1, S1PR agonists did not induce expression of the myofibroblast marker α-smooth muscle actin. However, TGF-β1, S1P, and FTY720-P caused robust stimulation of extracellular matrix (ECM) synthesis and increased pro-fibrotic marker gene expression including connective tissue growth factor. Ponesimod showed limited and SEW2871 showed no pro-fibrotic potential in these readouts. Analysis of pro-fibrotic signaling pathways showed that in contrast to TGF-β1, S1PR agonists did not activate Smad2/3 signaling but rather activated PI3K/Akt and ERK1/2 signaling to induce ECM synthesis. The strong induction of ECM synthesis by the nonselective agonists S1P and FTY720-P was due to the stimulation of S1P₂ and S1P₃ receptors, whereas the weaker induction of ECM synthesis at high concentrations of ponesimod was due to a low potency activation of S1P₃ receptors. Finally, in normal human lung fibroblast-derived myofibroblasts that were generated by TGF-β1 pretreatment, S1P and FTY720-P were effective stimulators of ECM synthesis, whereas ponesimod was inactive, because of the down-regulation of S1P₃R expression in myofibroblasts. These data demonstrate that S1PR agonists are pro-fibrotic via S1P₂R and S1P₃R stimulation using Smad-independent pathways.     

Cell Adhesion Induces the Plasminogen Activator Inhibitor-1 Gene Expression through Phosphatidylinositol 3-Kinase/Akt Activation in Anchorage Dependent Cells

Type-I plasminogen activator inhibitor (PAI-1) is the primary inhibitor of both tissue- and urokinase-type plasminogen activators (t-PA, u-PA) and is thus a primary regulator of plasminogen activation and possibly of extracellular proteolysis. In anchorage-dependent cells, the PAI-1 gene was regulated by cell adhesion. PAI-1 gene expression was induced more evidently in cells adhered to the culture plate than in nonadherent cells. In this study, we investigated the signal pathway of the PAI-1 gene expression regulated by cell adhesion. We found the induction of both PAI-1 mRNA and protein, when cells adhered to culture dish, was inhibited by the PI-3 kinase specific inhibitors (Ly294002 and wortmannin). The cells seeded on collagen-1 coated plate with low serum further demonstrated that the PAI-1 gene expression was prolonged by the cell adhesion. The above-mentioned PI-3 kinase specific inhibitors also blocked the PAI-1 maintenance when cell adhered to collagen-1 coated plate. In addition, we found that both PI-3 kinase and its downstream molecule, Akt, were activated more evidently in adherent cells than in nonadherent cells. Furthermore, we transfected antisense oligodeoxynucleotides of Akt (AS-ODN-Akt) into cells to block the expression of Akt and found that the induction of PAI-1 mRNA was also inhibited. Hence, we conclude that the induction of PAI-1 gene expression is cell adhesion dependent and is through PI-3 kinase and Akt activation.     

Characterization of a Small Molecule Inhibitor of Plasminogen Activator Inhibitor Type 1 That Accelerates the Transition into the Latent Conformation

A novel class of small molecule inhibitors for plasminogen activator inhibitor type 1 (PAI-1), represented by AZ3976, was identified in a high throughput screening campaign. AZ3976 displayed an IC₅₀ value of 26 μm in an enzymatic chromogenic assay. In a plasma clot lysis assay, the compound was active with an IC₅₀ of 16 μm. Surprisingly, AZ3976 did not bind to active PAI-1 but bound to latent PAI-1 with a K_D of 0.29 μm at 35 °C and a binding stoichiometry of 0.94, as measured by isothermal calorimetry. Reversible binding was confirmed by surface plasmon resonance direct binding experiments. The x-ray structure of AZ3976 in complex with latent PAI-1 was determined at 2.4 Å resolution. The inhibitor was bound in the flexible joint region with the entrance to the cavity located between α-helix D and β-strand 2A. A set of surface plasmon resonance experiments revealed that AZ3976 inhibited PAI-1 by enhancing the latency transition of active PAI-1. Because AZ3976 only had measurable affinity for latent PAI-1, we propose that its mechanism of inhibition is based on binding to a small fraction in equilibrium with active PAI-1, a latent-like prelatent form, from which latent PAI-1 is then generated more rapidly. This mode of action, with induced accelerated latency transition of active PAI-1 may, together with supporting x-ray data, provide improved opportunities for small molecule drug design in the hunt for therapeutically useful PAI-1 inhibitors.     

原发性及狼疮性肾病综合征患者血清PAI-1、Lp(a)水平变化及其临床价值探讨

目的:探讨原发性及狼疮性肾病综合征患者纤溶酶原激活物抑制因子1(PAI-1)和血清脂蛋白a[Lp(a)]的水平变化及其检测的临床应用价值。方法:选取病理类型明确,临床初诊为肾病综合征的患者138例。其中原发性肾病综合征70例,为PNS组;系统性红斑狼疮继发性肾病综合征患者68例,为LNS组。同期选取本院健康体检正常者64例,为正常对照NC组。全自动生化分析仪检测各组血清Lp(a)和血脂等指标;酶联免疫吸附(Elisa)法测定血清PAI-1水平。结果:1与NC组比较,血清Lp(a)和PAI-1水平在PNS和LNS两组中均显著升高(P0.05),PNS组比LNS组升高更为明显,差异有统计学意义(P0.05);2LP(a)与PAI-1秩相关系数(rs)分析,在PNS组中r_s=0.328,P=0.006,LNS组中r_s=0.439,P=0.006;3二元logistic回归分析表明,LP(a)和PAI-1均是PNS和LNS的危险因素;4ROC曲线分析表明,血清Lp(a)、PAI-1对PNS和LNS诊断的ROC曲线下面积(AUC~(ROC))分别为0.895、0.874和0.848、0.813,两者联合检测对PNS和LNS诊断的AUC~(ROC)分别为0.947和0.919。结论:血清Lp(a)与PAI-1水平在PNS和LNS患者体内均明显升高,PNS患者升高更为显著;Lp(a)与PAI-1水平在PNS和LNS患者中均显著正相关;LP(a)和PAI-1均是PNS和LNS的危险因素,两者水平的变化与PNS和LNS的发生相关。联合检测Lp(a)与PAI-1水平对PNS和LNS的诊治具有一定的临床应用价值。     

血清血管细胞黏附分子-1、纤溶酶原激活物抑制物-1、血管生成素样蛋白8与妊娠期糖尿病患者妊娠结局的关系研究

摘要 目的：探讨血清血管细胞黏附分子-1（VCAM-1）、纤溶酶原激活物抑制物-1（PAI-1）、血管生成素样蛋白8（ANGPTL8）与妊娠期糖尿病（GDM）患者妊娠结局的关系。方法：选择2019年4月~2021年3月期间陕西中医药大学第二附属医院收治的GDM孕妇136例作为研究组。选择同时期来陕西中医药大学第二附属医院产检的健康孕妇120例作为对照组。收集研究组患者的人口学及临床资料,采用酶联免疫吸附法检测两组孕妇的血清VCAM-1、PAI-1、ANGPTL8水平,观察两组孕妇的妊娠结局情况。研究组孕妇根据妊娠结局情况分为妊娠结局不良组和妊娠结局良好组,采用单因素及多因素Logistic回归分析GDM孕妇妊娠结局不良的影响因素。结果：研究组的血清VCAM-1、PAI-1、ANGPTL8水平高于对照组（P<0.05）。研究组的妊娠结局不良总发生率高于对照组（P<0.05）。单因素分析结果显示,GDM孕妇妊娠结局不良与年龄、产前体质量指数（BMI）、糖化血红蛋白（HbAlc）、空腹血糖（FBG）、空腹胰岛素（FINS）、总胆固醇（TC）、胰岛素抵抗指数（HOMA-IR）、糖尿病家族史、分娩史、居住地、VCAM-1、PAI-1、ANGPTL8水平有关（P<0.05）。多因素Logistic回归分析显示,年龄≥35岁、产前BMI≥28 kg/m²、HbAlc水平较高、居住地为城镇、VCAM-1、PAI-1、ANGPTL8水平升高均是GDM孕妇妊娠结局不良的影响因素（P<0.05）。结论：GDM孕妇血清VCAM-1、PAI-1、ANGPTL8水平异常升高,且三者均为GDM孕妇妊娠结局的影响因素,值得临床关注。