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PAI-1 Gene (pai-1 + gene)

Distribution by Scientific Domains

Medical Sciences	88%

Terms modified by PAI-1 Gene

pai-1 gene expression

pai-1 gene polymorphism

Selected Abstracts

E2F1-mediated transcriptional inhibition of the plasminogen activator inhibitor type 1 gene

FEBS JOURNAL, Issue 18 2001
Magdalena Koziczak
,Gene expression of the plasminogen activation system is cell-cycle dependent. Previously, we showed that ectopic expression of E2F1 repressed the plasminogen activator inhibitor type 1 (PAI-1) promoter in a manner dependent on the presence of DNA-binding and transactivation domains of E2F1 but independent of binding to pocket-binding proteins, suggesting a novel mechanism for E2F-mediated negative gene regulation [Koziczak, M., Krek, W. & Nagamine, Y. (2000) Mol. Cell. Biol.20, 2014,2022]. However, it remains to be seen whether endogenous E2F can exert a similar effect. We report here that down-regulation of PAI-1 gene expression correlates with an increase in endogenous E2F activity. When cells were treated with a cdk2/4-specific inhibitor, which maintains E2F in an inactive state, the decline of serum-induced PAI-1 mRNA levels was suppressed. In mutant U2OS cells expressing a temperature-sensitive retinoblastoma protein (pRB), a shift to a permissive temperature induced PAI-1 mRNA expression. In U2OS cells stably expressing an E2F1-estrogen receptor chimeric protein that could be activated by tamoxifen, PAI-1 gene transcription was markedly reduced by tamoxifen even in the presence of cycloheximide. These results all indicate that endogenous E2F can directly repress the PAI-1 gene. DNase I hypersensitive-site analysis of the PAI-1 promoter suggested the involvement of conformation changes in chromatin structure of the PAI-1 promoter. 5, deletion analysis of the PAI-1 promoter showed that multiple sites were responsible for the E2F negative regulation, some of which were promoter dependent. Interestingly, one of these sites is a p53-binding element. [source]

Mice Lacking the Plasminogen Activator Inhibitor 1 Are Protected from Trabecular Bone Loss Induced by Estrogen Deficiency

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2000
E. Daci
Abstract Bone turnover requires the interaction of several proteases during the resorption phase. Indirect evidence suggests that the plasminogen activator/plasmin pathway is involved in bone resorption and turnover, and recently we have shown that this cascade plays a role in the degradation of nonmineralized bone matrix in vitro. To elucidate the role of the plasminogen activator inhibitor 1 (PAI-1) in bone turnover in vivo, bone metabolism was analyzed in mice deficient in the expression of PAI-1 gene (PAI-1,/,) at baseline (8-week-old mice) and 4 weeks after ovariectomy (OVX) or sham operation (Sham) and compared with wild-type (WT) mice. PAI-1 inactivation was without any effect on bone metabolism at baseline or in Sham mice. However, significant differences were observed in the response of WT and PAI-1,/, mice to ovariectomy. The OVX WT mice showed, as expected, decreased trabecular bone volume (BV/TV) and increased osteoid surface (OS/BS) and bone formation rate (BFR), as assessed by histomorphometric analysis of the proximal tibial metaphysis. In contrast, no significant change in any of the histomorphometric variables studied was detected in PAI-1,/, mice after ovariectomy. As a result, the OVX PAI-1,/, had a significantly higher BV/TV, lower OS/BS, lower mineral apposition rate (MAR) and BFR when compared with the OVX WT mice. However, a comparable decrease in the cortical thickness was observed in OVX PAI-1,/, and WT mice. In addition, the cortical mineral content and density assessed in the distal femoral metaphysis by peripheral quantitative computed tomography (pQCT), decreased significantly after ovariectomy, without difference between PAI-1,/, mice and WT mice. In conclusion, basal bone turnover and bone mass are only minimally affected by PAI-1 inactivation. In conditions of estrogen deficiency, PAI-1 inactivation protects against trabecular bone loss but does not affect cortical bone loss, suggesting a site-specific role for PAI-1 in bone turnover. [source]

Gene polymorphisms of tissue plasminogen activator and plasminogen activator inhibitor-1 in Turkish patients with generalized aggressive periodontitis

JOURNAL OF CLINICAL PERIODONTOLOGY, Issue 4 2007
Gülnur Emingil
Abstract Aim: Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) have important roles in proteolytic events in periodontitis. The aim of this study was to investigate TPA and PAI-1 gene polymorphisms in relation to susceptibility to generalized aggressive periodontitis (G-AgP). Methods: Genomic DNA was obtained from peripheral blood of 90 G-AgP patients and 154 periodontally healthy subjects. 4G/5G polymorphism in the promoter region of the PAI-1 gene and Alu-repeat insertion/deletion (I/D) polymorphism in intron 8 of the TPA gene were genotyped by polymerase chain reaction and endonuclease digestion. Results: The genotype distributions of TPA and PAI-1 genes were similar between G-AgP and healthy subjects (p>0.05). The distribution of TPA genotypes in G-AgP patients was 33.4% D/D, 44.4% I/D, and 22.2% I/I and was 26.3% D/D, 40.4% I/D, and 33.3% I/I in healthy subjects. The D allele was 55.6% in G-AgP and 46.6% in healthy subjects. There was a significant difference among study groups in D allele frequencies (p=0.044). The PAI-1 genotype distribution in G-AgP was 29.1% 4G/4G, 43.0% 4G/5G, and 27.9% 5G/5G, while it was 35.7% 4G/4G, 43.8% 4G/5G, and 20.5% 5G/5G in healthy subjects. Conclusion: These data suggest that the D polymorphic allele of TPA gene polymorphism could be associated with susceptibility to G-AgP in Turkish subjects. [source]

Inhibition of plasminogen activator inhibitor-1 expression by siRNA in rat hepatic stellate cells

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 12 2008
Ping-Fang Hu
Abstract Background and Aim:, The plasminogen activator/plasmin system is known to regulate the extracellular matrix turnover. The aim of this study was to detect the role of plasminogen activator inhibitor-1 (PAI-1) during liver fibrogenesis and investigate the functional effects of PAI-1 gene silencing in rat hepatic stellate cells (HSCs) using small interfering RNA (siRNA). Methods:, Hepatic fibrosis in rats was induced through serial subcutaneously injections of CCl4 and the expression of PAI-1 was detected by immunohistochemistry and reverse transcription,polymerase chain reaction (PCR). PAI-1 siRNA molecules were constructed and transiently transfected into HSC-T6 using the cell suspension transfection method. The pSUPER RNA interfering system was used to establish the HSC stable cell line pSUPER-shPAI. Expression of alpha-smooth muscle actin, transforming growth factor-beta, tissue inhibitor of metalloproteinases-1, and collagen types I and III were evaluated by real-time PCR. Cell proliferation and the cell cycle were determined by the methyl thiazolyl tetrazolium (MTT) method and flow cytometry. Collagen content in HSCs supernatant was evaluated by enzyme-linked immunosorbent assay. Results:, The results showed that PAI-1 was upregulated during liver fibrosis, and its expression was closely correlated with the deposition of collagens. SiRNA molecules were successfully transfected into HSCs and induced inhibition of PAI-1 expression time dependently. Moreover, PAI-1 siRNA treatment downregulated alpha-smooth muscle actin, transforming growth factor-beta, tissue inhibitor of metalloproteinases-1 expression, and inhibited collagen types I and III synthesis both at the mRNA and protein level in transiently and stably transfected HSCs. Conclusions:, This study suggests a significant functional role for PAI-1 in the development of liver fibrosis and that downregulating PAI-1 expression might present as a potential strategy to treat liver fibrosis. [source]

The 4G-allele of the PAI-1 gene is not consistently associated with a higher prevalence of coronary stenosis

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2004
N. C. W. Ter Bogt
No abstract is available for this article. [source]

PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects

BRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2000
Rafael Seguí
Impaired fibrinolysis as a result of increased plasminogen activator inhibitor-1 (PAI-1) levels in plasma is a common finding in patients with deep vein thrombosis (DVT). A 4G/5G polymorphism in the promoter region of the PAI-1 gene has been reported to influence the levels of PAI-1. The 4G allele was found to be associated with higher plasma PAI-1 activity (act), but contradictory results on the incidence of the 4G allele in DVT patients have been reported. The aim of this study was to analyse whether the PAI-1 promoter 4G/5G genotype increases the risk of venous thrombosis in subjects with thrombophilic defects, and to determine the distribution of the PAI-1 4G/5G genotype and its relation to plasma PAI-1 levels in 190 unrelated patients with DVT in comparison with a control group of 152 healthy subjects. No differences between the 4G/5G allele distribution in the DVT group (0·43/0·57) and in the control group (0·42/0·58) were observed. However, the presence of the 4G allele significantly increased the risk of thrombosis in patients with other thrombophilic defects. Significantly higher PAI-1 levels were observed in DVT patients than in the controls. Our results also showed significant differences in the plasma levels of PAI-1 antigen (ag) and PAI-1 act among the 4G/5G genotypes in DVT patients. A multivariate analysis revealed that, in the DVT group, PAI-1 ag levels were influenced by the 4G allele dosage, triglyceride levels and body mass index (BMI). The influence of the 4G allele dosage on PAI-1 levels was independent of the triglyceride levels and BMI. In the control group, no significant correlation between PAI-1 levels and 4G allele dosage was observed. In conclusion, the PAI-1 promoter polymorphism was found to have an influence on PAI-1 levels in DVT patients and on the risk of venous thrombosis in subjects with other genetic thrombophilic defects. [source]

A-G-4G haplotype of PAI-1 gene polymorphisms ,844 G/A, HindIII G/C, and ,675 4G/5G is associated with increased risk of ischemic stroke caused by small vessel disease

ACTA NEUROLOGICA SCANDINAVICA, Issue 2 2009
M. G. Adamski
Background,,, Plasminogen activator inhibitor type 1 (PAI-1) is the major inhibitor of fibrinolysis. It was reported that PAI-1 gene polymorphisms affected PAI-1 level and might therefore influence the risk of vascular diseases, including stroke. We studied the association of three common polymorphisms in PAI-1 gene (,844 G/A, ,675 4G/5G, and HindIII G/C) with the odds of different causes of ischemic stroke. Methods,,, We studied 390 patients with ischemic stroke due to large vessel disease (n = 117), small vessel disease (n = 121), and cardioembolism (n = 152) as well as 291 controls. The etiology of ischemic stroke was established using TOAST criteria. PAI-1 polymorphisms were genotyped with restriction fragment length polymorphism and single strand conformation polymorphism method. Results,,, A-G-4G haplotype of PAI-1 gene was found more frequently in stroke patients with small vessel disease than in control subjects (44.9% vs 35.7%; P = 0.02). No association was found between investigated genotype or allele frequencies and distinct causes of ischemic stroke. Conclusions,,, Our results demonstrate that A-G-4G PAI-1 gene haplotype is associated with increased risk of small vessel disease stroke, but this study does not support an association of ,844 G/A, ,675 4G/5G, and HindIII G/C PAI-1 gene polymorphisms with particular etiology of ischemic stroke. [source]

Plasminogen activator inhibitor-1 and asthma: role in the pathogenesis and molecular regulation

CLINICAL & EXPERIMENTAL ALLERGY, Issue 8 2009
Z. Ma
Summary Plasminogen activator inhibitor (PAI)-1 is a major inhibitor of the fibrinolytic system. PAI-1 levels are markedly increased in asthmatic airways, and mast cells (MCs), a pivotal cell type in the pathogenesis of asthma, are one of the main sources of PAI-1 production. Recent studies suggest that PAI-1 may promote the development of asthma by regulating airway remodelling, airway hyperresponsiveness (AHR), and allergic inflammation. The single guanosine nucleotide deletion/insertion polymorphism (4G/5G) at ,675 bp of the PAI-1 gene is the major genetic determinant of PAI-1 expression. Plasma PAI-1 level is higher in people with the 4G/4G genotype than in those with the 5G/5G genotype. A strong association between the 4G/5G polymorphism and the risk and the severity of asthma has been suggested. Levels of plasma IgE and PAI-1 and severity of AHR are greater in asthmatic patients with the 4G/4G genotype than in those with the 5G/5G genotype. The PAI-1 promoter with the 4G allele renders higher transcription activity than the PAI-1 promoter with the 5G allele in stimulated MCs. The molecular mechanism for the 4G allele-mediated higher PAI-1 expression is associated with greater binding of upstream stimulatory factor-1 to the E-box adjacent to the 4G site (E-4G) than to the E-5G. In summary, PAI-1 may play an important role in the pathogenesis of asthma. Further studies evaluating the mechanisms of PAI-1 action and regulation may lead to the development of a novel prognostic factor and therapeutic target for the treatment and prevention of asthma and other PAI-1-associated diseases. [source]