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. Multiple logistic regression analysis identified sex, angina pectoris, and PAI-1 as independent determinants of hyperadiponectinemia. 4G/4G genotype associated with elevated plasma PAI-1 in Chinese with and without hypertension. Contribution of PAI-1 genotype seemed larger in women. In hypertensives carrying the 4G/4G genotype, higher TG was correlated with higher PAI-1. 4G/5G polymorphism of the PAI-1 gene might be associated with low-density lipoprotein particle size. A proteolytic effect for PAI-1 regulates cell invasiveness in desmoid tumor. Arsenite inhibited the thrombomodulin (TM) mRNA expression and reduced the TM antigen level in microvascular endothelial cells, but not umbilical vein endothelial cells, suggesting a role in Blackfoot disease, a peripheral vascular occlusive disease. Blood levels not altered in HIV patients, with or without HAART. Both adipose tissue and blood PAI-1 levels were positively associated with TNFRSF1A and TNFRSF1B in obesity. C5a stimulates production of plasminogen activator inhibitor-1 in human mast cells and basophils. CO2 increased mesothelial cell PAI-1 expression involving a transcriptional mechanism. These findings might provide a mechanism for adhesion formation and cancer progression following laparoscopic surgery. Calcium appeared to have a critical role in the regulation of the HIF system and subsequent activation of the PAI-1 gene expression. Cell adhesion regulates plasminogen activator inhibitor-1 gene expression in anchorage-dependent cells; vitronectin and fibronectin, as components of ECM, may be the factors involved in the regulation of PAI-1 gene expression. Data describe the cyclic variation and distribution of urokinase plasminogen activator (uPA), uPA receptor and plasminogen activator inhibitor 1 (PAI-1) mRNA in normal endometrium. Distortion of autocrine transforming growth factor beta signal accelerates malignant potential by enhancing cell growth as well as PAI-1 and VEGF production in human hepatocellular carcinoma cells. During infusion of triacylglycerol, PAI-1 increased to approximately 2.6 fold higher levels while tPA and adipsin were unaffected; changes in sVCAM-1 were significantly correlated with those seen for PAI-1. During weight loss, after gastric restrictive surgery, inflammatory mediators remain elevated for at least 3 months. postoperatively, suggesting initially an ongoing inflammatory state. ERalpha activates the PAI-1 promoter through a proximal ERE (-427) & possibly additional EREs. ERbeta suppresses the promoter construct via an unidentified mechanism. Elevated PAI-1 levels are associated with target organ damage in subjects with newly diagnosed arterial hypertension. Ethnic differences in the PAI-1 4G/5G polymorphism along with corresponding differences in circulating PAI-1 levels were determined. Gelsolin and plasminogen activator inhibitor-1 have roles as Ap3A-binding proteins. Genotypes of PAI-1 4G/5G and MTHFR C677T or plasma concentrations of PAI-1 had no effect on the incidence of ONFH in Japanese subjects. Gly-BSA increases DNA binding activity of Smad3 and that it stimulates PAI-1 transcription through Smad-binding CAGA sequences in the PAI-1 promoter in human mesangial cells. High expression of plasminogen activator inhibitor, type I is associated with melanoma. Human breast adenocarcinoma cell lines promote angiogenesis by providing cells with uPA-PAI-1 and by enhancing their expression. Hyperglycemic siblings of type II diabetic patients have increased blood levels, central obeisty and insulin resistance compared with their paired normoglycaemic sibling. Hypoxia enhances the expression of plasminogen activator inhibitor-1. Identification of a tightly regulated hypoxia-response element in the promoter of human plasminogen activator inhibitor-1. In children with sepsis-induced multiple organ failure, a cytokine-associated increase in circulating PAI-1 release & systemic activity was predicted. Increased PAI-1 activity was associated with cardiovascular, renal, and hepatic failure. In health centenarians plasma PAI-1 not associated with degree of insulin resistance. Analysis of genotype did not explain PAI-1 levels. In patients with type 2 diabetes mellitus, the PAI-1 4G/5G promoter polymorphism does not predict PAI-1 plasma levels and is not associated with common metabolic parameters besides fibrinogen levels. Increase of this protein in keloid fibroblasts may account for their elevated collagen accumulation in fibrin gel cultures. Increased PAI-1 levels were found from eary 2d trimester through labor and decreased after delivery. Elevated PAI-1 serves to counteract the enhanced fibrinolysis seen during labor. Increased PAI-1 levels were significantly related to insulin resistance in a Japanese general population. PAI-1 levels are associated with insulin resistance, irrespective of obesity. Induction of PAI-1 by exposure of lung epithelial cells to uPA is a newly recognized pathway by which PAI-1 could regulate local fibrinolysis in lung inflammation or neoplasia. Induction of PAI-1 gene expression is cell adhesion dependent and is through PI-3 kinase and Akt activation. Lys(88), Asp(89), Lys(176) & His(229) are the major residues of the PAI-1 conformational epitope. Lysine(88) & aspartic acid(89) are on the loop between alpha-helix D & beta-strand 2A. They undergo big conformational changes during latency conversion. MEK1,2 response element that mediates angiotensin II-stimulated PAI-1 promoter activation and shows that activation of this element requires Sp1 and AP-1 co-activation. MMP-13, uPA, and PAI-1 antigen levels were determined in the synovium of patients with osteoarthritis. Oncostatin M and interleukin-1 regulate the PAI-1 gene expression via up-regulating c-fos levels and subsequent binding of c-fos/c-jun heterodimers to the proximal element of the PAI-1 gene. Our results support a protective effect of the PAI-1 4G allele against stroke; notable given the direct relationship between stroke and PAI-1 activity. We hypothesize that local increase in tissue PAI-1 associated with the 4G allele may stabilize plaques. PAI-1 4G/5G promoter polymorphism alone is not associated with ischemic stroke. PAI-1 also plays a pivotal role in progressive renal disease, both glomerulosclerosis and tubulointerstitial fibrosis. PAI-1 and IL-8 secretion are increased by glucose. PAI-1 appears to stabilize the chemoattractant form of IL-8 at the cell surface, prevents shedding of proteoglycan, and maintains the chemoattractant gradient in cultured vascular endothelial cells. PAI-1 expressed recombinantly or naturally by human cell lines displays heterogeneous glycosylation pattern of sites at N209 and N265, while that at N329 is not utilised. PAI-1 gene activation by TNF-alpha apparently is yet to be defined for the location of the response element and/or the signaling pathway. BAEC responded to TNF-alpha stimulation with activation of the MAP kinases and the NFkappaB transcriptional factors. PAI-1 has roles in tumour growth, invasion, and metastasis [review]. PAI-1 inhibits plasminogen activators by forming stable complexes endocytosed by LDL receptor superfamily mechanism and circulates in plasma and latently in platelets but is also secreted and deposited into matrix by cells to participate in tissue repair. PAI-1 is induced by oncostatin M in lung tumor cells. PAI-1 levels and activity were increased in lean polycystic ovary syndrome women and these were directly correlated with insulin resistance. PAI-1 levels are elevated in android obesity, which suggests that increased oxidative stress may represent a biochemical link between android obesity and an increased risk for cardiovascular disease. PAI-1 mRNA was detected in 13 of 16 prostatisc carcinomas and in 8 of 9 benign hyperplasias. PAI-1 may have a role in metastasis of esophageal squamous cell carcinoma. PAI-1 mutants inhibit neutrophil elastase and cathepsin G. PAI-1 polymorphism in the promoter region is not a risk factor for myocardial infarction in Caucasians with type 2 diabetes mellitus. PAI-1 polymorphisms interact with known environmental risk factors (chronic hyperglycaemia, obesity, etc.) to induce a more severe insulin-resistant metabolic profile in overweight subjects, and to further increase risk for CHD in diabetic subjects. PAI-1 production by endothelial cells is affected differently by calcitriol and paricalcitol. PAI-1 was determined in myocardial infarction and re-infarction patients along with other parameters relevant for the Syndrome X. PAI-1, via interaction with both Act-4 and uPA, may function as a modulator of the mononuclear phagocyte response, not only in inflammation but also in tumor invasion and metastasis. PAI-1/ tPA imbalance is associated with myocardial infarction at young age in Japanese men. PAI-1:Ag levels were higher in symptomatic thrombophilia patients and related to the 4G/5G polymorphism, with significantly higher values in the 4G/4G carriers. PAI-I has roles in the pathogenesis of cardiovascular disease [review]. PAI-I modulates glioma cell invasion and motility through extracellular matrix components. PAI1 polymoprhism in the promoter region is not associated with the risk of cardiovascular disease. PPARgamma can reduce plasminogen activator inhibitor type 1 production in vascular endothelial cells directly by repression of transcription. Plasminogen activator inhibitor type 1 promotes the self-association of vitronectin into complexes. Positive association of IL-6 GG genotype with hypertension and elevated plasma PAI-1 in normotensive individuals in Chinese in Taiwan. IL-6 gene promoter G-174C polymorphism may affect regulation of PAI-1 and blood pressure through inflammatory mechanism. REVIEW of factors which influence PAI-1 levels and the possible role of PAI-1 polymorphisms in the acute phase response and cardiovascular diseases. REVIEW: studies defining the binding sites of vitronectin and PAI-1 and binding affinities in the formation of larger PAI-1/Vtn complexes. Reactivve oxygen species production, NAD(P)H oxidase activity, mitochondrial membrane potential, AP-1 activity, PAI-1 mRNA expression, and proliferation and migration of human vascular smooth muscle cells. Recent data in this review suggest that PAI-1 contributes directly to the complications of obesity, including type 2 diabetes, coronary arterial thrombi, and may even influence the accumulation of visceral fat. Recent large Japanese case-control studies identified connexin-37 (GJA-4), plasminogen activator inhibitor-1 (PAI-1), and stromelysin-1 (MMP-3) polymorphisms as risk factors for myocardial infarction. Sphingosylphosphorylcholine induces PAI-1 production through a G protein-coupled calcium increase and downstream kinase signaling events in cultured human dermal fibroblasts. Study of the association between 4G/4G and 4G/5G genotypes and the site of thrombosis suggests an association with thrombosis in vessels of internal organs especially in the portal veins. TGF-beta-stimulation of transcription of PAI-1 is inhibited by VEGF, and TGF-beta phosphorylation of Smad2/3, an obligatory step of intracellular TGF-beta signaling, is suppressed by VEGF. TGFbeta was the only growth factor tested that was able to exceptionally up-regulate PAI-1, mainly in dystrophic satellite cells rather than normal myoblasts. The 4G-allele of the PAI-1 gene is not consistently associated with a higher prevalence of coronary stenosis. The cleavage and inactivation of PAI-1 by generated thrombin is proposed to be responsible for the shortening of clot lysis time by Ca2+ and for coagulation-associated over-expression of fibrinolysis, which was suppressed by aPC. The common -675 4G/5G polymorphism is strongly associated with obesity. The data presented identify new determinants of this inhibitor's latency transitions and provide general insight into the characteristic loop-sheet interactions in serpins. The distribution of PAI-1 promoter 4G/5G polymorphism in Chinese differs from that in Caucasians. PAI-1 promoter 4G/5G polymorphism does not alter basic transcription activity and 4G promoter has increased response to IL-1. The expression of PAI-1 protein and PAI-1 mRNA is increased in HCC and contributes to the invasion, metastasis and prognosis of HCC. The expression of PAI-1 was significantly correlated with gastric tumor size, depth, lymph node involvement, differentiation, &vascular invasion. The induction of increased PAI-1 expression in human arterial smooth muscle cells by growth factors implicated in accelerated atherogenesis is independent of the PAI-1 4G/5G polymorphism. The level of type I plasminogen activator inhibitor-1 (PAI-1) does not correlate with cerebrospinal fluid to serum albumin ratio, suggesting an unimportant role for PAI-1 in HIV-induced blood-brain-barrier disruption. The levels of P-selectin, tPA antigen, and PAI-1 activity were all significantly higher in stroke patients compared with controls. The low density lipoprotein receptor-related protein is a motogenic receptor for plasminogen activator inhibitor-1. The morning increase in PAI-1 is more pronounced among homozygotes for the 4G allele compared with the other genotypes. Homozygosity for the 4G allele is associated with increased PAI-1 levels during the morning only. The observations suggest TZDs inhibit TNFalpha-mediated PAI-1 induction independent of inducible PPARgamma activation. There was a positive correlation between uPA and PAI-1 antigen levels and clinicopathological parameters such as grade (p < 0.001 and p = 0.01, respectively). These data demonstrate that TNF-alpha rather than IL-6 stimulates an increase in PAI-1 mRNA in the subcutaneous adipose tissue, suggesting that TNF-alpha may be involved in the pathogenesis of related metabolic disorders. These results are the first to demonstrate that an orally active PAI-1 inhibitor can reduce plasma PAI-1 activity while maintaining normal platelet aggregation and coagulation. This article maps the epitopes of a monoclonal antibody protecting this inhibitor against inactivating agents. This study suggests that PAI-1 has a role in risk of MI in the presence of underlying insulin resistance. A significant interaction between insulin or proinsulin and the -675 4G/5G polymorphism was observed in risk for MI. Together with low birth weight, increased plasma PAI-1-act levels in early pubertal precocious pubarche may indicate a greater risk of developing hyperinsulinemic-hyperandrogenism features of polycystic ovary syndrome. Transforming growth factor-beta1 produced by ovarian cancer cell line HRA stimulates attachment and invasion through an up-regulation of plasminogen activator inhibitor type-1 in human peritoneal mesothelial cells. Type 1 plasminogen activator inhibitor (PAI-1) 4G/5G gene polymorphism might affect the plasma PAI-1 levels related to exhaustion severity. With the 5G/5G polymorphism, exhausted subjects might have less fibrinolytic capacity than non-exhausted subjects. Unregulated plasmin hyperactivity due to decreased inhibition by PAI-1 may play an important role in coronary aneurysm formation. Upon reactive center loop cleavage and loop insertion into the body of PAI-1, resonances assigned to Trp86 and Trp139 undergo large downfield chemical shifts consistent with major changes observed in the crystal structures of active and cleaved PAI-1. Upstream elements are important regulators of growth factor-initiated PAI-1 transcription (as predicted from the identification of PAI-1 as a direct upstream factor target gene) and the associated epithelial migratory response. VEGF and PAI-1 interact and may have roles in progression of node-negative breast cancer. A decreased risk of MI or stroke among young women carrying the 4G allele of the PAI-1 4G/5G polymorphism. A genetic variant of the plasminogen activator inhibitor-1 (PAI-1) determines the risk of avascular osteonecrosis in glucocorticoid-treated patients. Agonists of PPAR alpha increased basal and insulin-stimulated PAI-1 antigen release with a mechanism involving gene transcription and requiring signaling through the ERK1/2 signaling pathway. Basic capacity of separated epithelial and stromal cells from all three types of tissue to release uPA, PAI-1, and suPAR without any paracrine influence, as in vivo. Cellular iron status regulates the expression of PAI-1 via mRNA stability and subsequently the cell-surface plasmin activity in cultured human lung fibroblasts. Continuous production of large amounts of active PAI-1 in platelets. Diurnal pattern in PAI-1 activity and t-PA in relation to the 4G/5G-polymorphism in the promoter of the PAI-1 gene. Elevated PAI-1 activity may be a factor in the increased cardiovascular morbidity seen in polycystic ovary syndrome. Evidence that locking PAI-1 in a transition state between active and latent conformations is associated with a displacement of alphahF, subsequently resulting in substrate behavior. Findings indicate that the LDL particles that reach the subendothelial space can induce an increased release of PAI-1 by endothelial cells into the vessel lumen. Findings suggest that PAI-1 plays a role in later (thrombotic) rather than an earlier (atherosclerotic) stage of cardiovascular disease process. First study to quantify discrete plasminogen activator inhibitor-1 elevations that persist in the setting of polycystic ovary syndrome even with normal or low ambient insulin levels. Formation of an inhibited serpin-proteinase complex as a single concerted transition of the serpin structure. Healthy persons and patients with previous myocardial infarction differed regarding coronary risk factors associated with PAI-1. Homozygosity for the ACE D allele is a risk factor for recurrent spontaneous miscarriages(RM); homozygosity for the ACE D and PAI-1 4G alleles additionally amplifies the RM risk; this may be exerted by their common effect to increase PAI-1 expression. Hypofibrinolytic genotypes of the PAI-1 gene are associated with the occurrence of mild preeclampsia. Hypoxia increased PAI-I mRNA levels in both normal peritoneal fibroblasts and adhesion fibroblasts. Hypoxia-dependent plasminogen activator inhibitor 1 expression is regulated by MAP kinases. Identified a 5' distal TNFalpha-responsive enhancer of the PAI-1 gene located 15 kb upstream of the transcription start site containing a conserved NFkappaB-binding site that mediates the response to TNFalpha. In vitro assays of basal transcription suggest no difference in the binding of nuclear proteins to the promoter and no difference in the transcriptional activities of the alleles of the PAI-1 4G/5G polymorphism. Increased PAI-1 activity in children with stable renal transplants is determined both by genetic factors and by metabolic factors, the latter mainly linked to the insulin resistance syndrome. Indication that PAI-1 gene is a direct target of EPAS1 and suggest the role of EPAS1 and Sp1 in the hypoxic response of cancer cells. Inhibition of Rho/Rho-kinase signaling downregulates the synthesis of PAI-1 in human monocytes. Interactions between the fibrinolytic and renin-angiotensin systems play an important role in the genetic architecture of plasma t-PAI-1. Mean transit time, the net quantitative turnover rate, and the sites of synthesis and catabolism. No evidence that subjects with 4G/4G polymorphism have higher PAI-1 levels on admission or 6 months after acute myocardial infarction. Levels of PAI-1 are related to concentrations of proinsulin-like molecules and of proinflammatory cytokines. No significant association between homozygosity for PAI-1 4G4G and risk of retinal vein occlusion. P53 binds to and regulates the promoter of PAI-1. Plasminogen activator inhibitor 1 (PAI-1) is converted by monoclonal antibodies to a substrate for tissue (tPA)- and urokinase plasminogen activators. Plasminogen activator inhibitor type 1 is required for the regulation of plasminogen activator-dependent, plasmin-independent processes, and expression critically modulates inflammation--REVIEW. Plasminogen activator inhibitor-1 (PAI-1) gene 4G/5G polymorphism is associated with coronary heart disease (CHD) in Chinese. Plasminogen activator inhibitor-1 distorts the catalytic domain of tissue-type plasminogen activator leading to the formation of stable serpin-proteinase complexes. Plasminogen activator inhibitor-1 has roles in wound healing, atherosclerosis, metabolic disturbances, tumor angiogenesis, chronic stress, bone remodeling, asthma, rheumatoid arthritis, fibrosis, glomerulonephritis and sepsis [review]. Plasminogen activator inhibitor-1 production was significantly higher in omental than in subcutaneous adipose tissue and in obese subjects was higher than in non-obese subjects in both subcutaneous and in omental adipose tissue. Plasminogen activator inhibitor-1(PAI-1) genotypic subtypes 4G/4G and 4G/5G in polycystic ovary syndrome(PCOS) were present with a statistically higher frequency and PCOS women had higher levels of PAI-1. Polymorphic in graft dysfunction after renal transplantation. Relationships among adult periodontitis, smoking, and a variation in the deletion/insertion (4G/5G) promoter polymorphism of the plasminogen-activator-inhibitor-1 (PAI-1) gene. Results strongly support that sTNF up-regulates in an autocrine manner PAI-1 and MMP-9 syntheses during promyelocyte to monocyte differentiation; in more advanced differentiated stages, released sTNF is not a major determinant of PAI-1 and MMP-9 syntheses. Review discusses the discovery, origin, properties and regulation of PAI-1, and then speculates about its potential role in vascular disease, fibrosis, obesity and the metabolic syndrome, and cancer. Serine (or cysteine) proteinase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1. Small, hormone-receptor-positive breast cancers (with a theoretical good prognosis) may carry an elevated risk of nodal involvement if accumulation of uPA-PAI-1 complexes is shown inside their tumour cells by means of immunohistochemistry. Study demonstrates that PAI-1 concentrations are higher in impaired glucose tolerance than in normal glucose tolerance subjects. The 4G/5G polymorphism may influence PAI-1 expression in obesity, with a crucial role in central but not peripheral adiposity. The G20210A prothrombin gene mutation and the PAI-1 5G/5G genotype have roles in early onset of severe preeclampsia. The PAI-1 level and the Chalkley count are independent prognostic markers for recurrence-free survival in patients with primary breast cancer, suggesting that the prognostic impact of PAI-1 is not only based on its involvement in angiogenesis. The in vitro migratory and invasive phenotype in breast and ovarian cancer cell lines is reduced by active PAI-1 due to its ability to inhibit plasminogen activation. The level of Smad6s can alter the level of TGF-beta and the subsequent induction of PAI-1 via a FoxD1 transcription site. The transcriptional response of the endogenous mPAI-1 promoter varies widely in terms of tissue specificity and magnitude of response to specific stimuli, angiotensin II, tgf-beta1, and LPS. UPA and PAI-1 have roles in progression and recurrence of breast cancer [review]. UPA:PAI-1 complex independently predicts the efficacy of adjuvant chemotherapy in patients with primary breast cancer. Upregulation of PAI-1, uPA, and tPA after long-term LDL exposure seems to be mediated by a delayed PKC activation associated with an increased PA inhibitory activity. Urokinase-type plasminogen activator (uPA) and type-1 inhibitor (PAI-I) complex has a role in breast cancer resistance to endocrine therapy independent of steroid hormone receptor status.
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