Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasminogen activator inhibitor-1 (PAI-1) is a serpin protease inhibitor that binds plasminogen activators (uPA and tPA) at a reactive center loop located at the carboxyl-terminal amino acid residues 320-351. The loop is stretched across the top of the active PAI-1 protein maintaining the molecule in a rigid conformation. In the latent PAI-1 conformation, the reactive center loop is inserted into one of the beta sheets, thus making the reactive center loop unavailable for interaction with the plasminogen activators. We truncated porcine PAI-1 at the amino and carboxyl termini to eliminate the reactive center loop, part of a heparin binding site, and a vitronectin binding site. The region we maintained corresponds to amino acids 80-265 of mature human PAI-1 containing binding sites for vitronectin, heparin (partial), uPA, tPA, fibrin, thrombin, and the helix F region. The interaction of "inactive" PAI-1, rPAI-1(23), with plasminogen and uPA induces the formation of a proteolytic protein with angiostatin properties. Increasing amounts of rPAI-1(23) inhibit the proteolytic angiostatin fragment. Endothelial cells exposed to exogenous rPAI-1(23) exhibit reduced proliferation, reduced tube formation, and 47% apoptotic cells within 48 h. Transfected endothelial cells secreting rPAI-1(23) have a 30% reduction in proliferation, vastly reduced tube formation, and a 50% reduction in cell migration in the presence of VEGF. These two studies show that rPAI-1(23) interactions with uPA and plasminogen can inhibit plasmin by two mechanisms. In one mechanism, rPAI-1(23) cleaves plasmin to form a proteolytic angiostatin-like protein. In a second mechanism, rPAI-1(23) can bind uPA and/or plasminogen to reduce the number of uPA and plasminogen interactions, hence reducing the amount of plasmin that is produced.
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PMID:A truncated plasminogen activator inhibitor-1 protein induces and inhibits angiostatin (kringles 1-3), a plasminogen cleavage product. 1111 16

Tissue plasminogen activator (tPA) promotes fibrinolysis, and impaired fibrinolysis is associated with atherosclerosis and thrombosis. Plasminogen activator inhibitor-1 (PAI-1) inhibits t-PA expression. The effects of acute laboratory stressors on tPA and tPA/PAI-1 complexes were assessed in a sample of 11 cardiac patients. Participants were randomly assigned to either a stress or relaxation condition at time 1, and the alternative condition at time 2. Blood samples were taken before (pre) and after (post) each session and participants completed a battery of psychological questionnaires. Two-way repeated-measures analysis of variance revealed a statistically significant decrease in tPA (P = 0.01) and tPA-PAI-1 complexes (P = 0.04) during the mental stress condition. Anger-in had a strong relationship to decreases in tPA/PAI-1 levels in the stress condition (r = 0.68, P < 0.05). Relaxation had no significant effect on tPA and tPA/PAI-1 levels. These data suggest that decreased fibrinolysis mediates the relationship between mental stress and atherosclerosis.
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PMID:Acute psychological stress decreases plasma tissue plasminogen activator (tPA) and tissue plasminogen activator/plasminogen activator inhibitor-1 (tPA/PAI-1) complexes in cardiac patients. 1113 73

In contrast to a reduced risk of coronary heart disease (CHD) with light to moderate alcohol consumption, heavy alcohol intake and binge drinking are associated with increased cardiovascular mortality. Alcohol has an acute and profound effect on fibrinolysis that may be relevant to the pathogenesis of CHD. The short-term effects of a low (two glasses, 250 mL, 20 g ethanol) and a high (six glasses, 750 mL, 60 g ethanol) intake of red wine were studied in male volunteers and compared to the intake of mineral water. To find a threshold for inhibition of fibrinolysis and to study a binge effect, a second experiment was performed comparing the intake of four (500 mL, 40 g ethanol) and eight (1000 mL, 80 g ethanol) glasses of red wine with mineral water. Plasminogen activator inhibitor-1 (PAI-1), tissue-type plasminogen activator (t-PA), plasmin-antiplasmin (PAP) complexes and clot lysis time were measured. In contrast to the circadian rhythm with an enhanced fibrinolysis in the evening that was found in the mineral water group, an intake above four glasses of wine inhibited fibrinolysis significantly. After the intake of two glasses no significant disturbance of the circadian rhythm was observed. Five hours after the consumption of six glasses of wine, a dramatic increase occurred of PAI-1 antigen (77 +/- 42 microg L-1 vs. - 5 +/- 10 microg L-1 in the mineral water controls; P < 0.001) and PAI-1 activity (27 +/- 15 U mL-1 vs. - 2 +/- 3 U mL-1 in mineral water controls; P < 0.001). Despite a rise in t-PA antigen, t-PA activity dropped (- 0.5 +/- 0.2 U mL-1 vs. - 0.1 +/- 0.2 in controls; P < 0.001) as did PAP complexes (- 103 +/- 55 microg L-1 vs. - 26 +/- 57 microg L-1 in controls; P < 0.01). After the consumption of eight glasses of wine, the clot lysis assay indicated continued inhibition of fibrinolysis the following morning. Drinking a large amount of alcohol in the evening results in an acute inhibition of fibrinolysis, persisting the following morning. This may predispose to accelerated atherosclerosis and set the stage for thrombotic coronary events, explaining the higher cardiovascular mortality risk in binge drinkers.
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PMID:Acute inhibitory effect of alcohol on fibrinolysis. 1116 56

Comprehensive studies of fibrinolysis in non-small cell lung carcinoma have been limited, and assignment of patients to high/low prognosis groups based on arbitrary cut-offs utilizing fibrinolytic measurements is unstandardized. This study was performed in 166 patients to examine the effects of cut-off values determined in three ways. Model 1 assigned patients to one of three equal groups (low, medium, high) based on fibrinolytic measurements made at diagnosis, Model 2 divided patients into low/high groups using median values, and Model 3 grouped according to the parameter being above/below normal range. In model 1, raised plasma fibrinogen, D-dimer and soluble fibrin were positively associated with poorer survival. In model 2, tissue plasminogen activator antigen was additionally related to poorer prognosis. Model 3 identified seven parameters as significantly related to survival, two not identified by the other models becoming significant [plasmin-antiplasmin, tissue plasminogen activator inhibitor-1 (PAI-1) antigen]. Using multivariate analysis, plasma fibrinogen level was the most uniformly significant parameter. Relative risk estimates indicated that raised plasma fibrinogen, soluble fibrin and D-dimer were associated with increased risk of death. Use of the normal/above normal cut-off is recommended to provide the maximum number of significant parameters relating to prognosis, and increased plasma D-dimer, PAI-1 antigen and fibrinogen were most closely related to survival/prognosis.
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PMID:Impact of the fibrinolytic enzyme system on prognosis and survival associated with non-small cell lung carcinoma. 1122 27

The present study represents a new insight into the Biguanides and the Prevention of the Risk of Obesity (BIGPRO) 1 study population at inclusion. This population, selected basically on the basis of a high waist-to-hip ratio (>/=0.95 for men and >/=0.80 for women), is supposed to represent a group of patients with insulin resistance. The present study was undergone to establish whether apolipoprotein C-III (apoC-III) and apolipoprotein E (apoE) associated with apo B (apoC-III LpB and apoE LpB, respectively), considered to be markers of remnant accumulation, play a role in the hypertriglyceridemia associated with insulin resistance and whether they are related to other biological abnormalities frequently observed in this syndrome. In this population, the concentration of the markers of remnant accumulation increases with triglyceride levels. Therefore, correlation studies were realized to assess the relative effect of insulin and the markers of remnant accumulation on triglyceride plasma level. As a first attempt, a simple correlation analysis revealed that insulin is positively related to the markers of remnant accumulation only in hypertriglyceridemic patients (triglycerides >/=1.7 mmol/L). To assess the independent contribution of these markers, insulin, and other parameters related to the plasma triglyceride concentration, a stepwise multiple regression analysis was run. Results revealed that insulin and the markers of remnant accumulation (specifically, apoE LpB) are independent contributors to the plasma triglyceride concentration. Markers of the endothelial damage, plasminogen activator inhibitor-1, tissue plasminogen activator, and von Willebrand factor, which are often increased in the case of insulin resistance, were tested for their correlation with the markers of remnant accumulation. Plasminogen activator inhibitor-1 is positively correlated with these markers only in hypertriglyceridemic male subjects. It is concluded that increased insulin levels found in insulin resistance syndrome are associated with an increased production of triglyceride-rich lipoproteins enriched in apoC-III and apoE. The accumulation of these remnants and/or their abnormal composition in apoC-III and apoE could be an explanation for the development of hypertriglyceridemia in this syndrome.
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PMID:Accumulation of triglyceride-rich lipoprotein in subjects with abdominal obesity: the biguanides and the prevention of the risk of obesity (BIGPRO) 1 study. 1123 21

The aim of this study was to determine the effects of ECM protein coatings and surface modification of PTFE on the ability of seeded human endothelial cells (EC) to secrete prostacyclin (PGI2), plasminogen inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA). PTFE surfaces were modified by a novel surface modification technique based on ammonia plasma. Fibronectin, collagen type-1 and gelatin-coated ammonia plasma modified PTFE and unmodified PTFE surfaces were employed and compared in this study. All ammonia plasma modified surfaces showed similar secretions of PGI2 compared to non-modified PTFE surfaces. With the exception of gelatin-coated modified PTFE, seeded EC seeded on all modified PTFE showed lower levels of PAI-1 secretion compared to those seeded on unmodified PTFE. The specific activity of t-PA secreted by EC seeded on ammonia plasma modified and fibronectin coated modified PTFE showed increases of 100 and 30%, respectively, when compared to their unmodified counterparts. Our studies show that EC seeded on modified PTFE have ability to secrete PGI2 that modulates the early phase of thrombus formation. Furthermore, superior t-PA profile, along with lower levels of PAl-1 suggest that ammonia plasma modification and use of appropriate ECM proteins can modulate antithrombotic and fibrinolytic properties of in vitro endothelialized vascular prostheses. Accordingly, these surfaces may be suitable to further develop protocols and other strategies for arterial and venous reconstruction.
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PMID:Antithrombotic and fibrinolytic system of human endothelial cells seeded on PTFE: the effects of surface modification of PTFE by ammonia plasma treatment and ECM protein coatings. 1133 19

Several studies have shown cardiovascular benefit in treating hypercholesterolemia with HMG-CoA reductase inhibitor. However, in addition to the lowering of cholesterol, the beneficial effects of this inhibitor reflect other pharmacological activities. Whether these beneficial effects are partly mediated by changes in fibrinolytic factors remains to be proven, since clinical studies on the effects of HMG-CoA reductase inhibitors on fibrinolytic factors have not yielded consistent results. The purpose of this study was to evaluate the effects of fluvastatin on fibrinolytic factors in hypercholesterolemic patients. After 6 weeks on a low-fat, low-cholesterol diet, 23 outpatients known to have primary hypercholesterolemia with low density lipoprotein cholesterol (LDL-C) > or = 130 mg/dl with at least 2 risk factors or fasting LDL-C > or = 160 mg/dl were selected for the study. Venous blood samples were collected at baseline and at 8 weeks after fluvastatin therapy (40 mg/day) to measure of tissue plasminogen activator (t-PA), plasminogen activators inhibitor-1 (PAI-1), fibrinogen, D-dimer and lipid profile. After 8 weeks of therapy, fluvastatin reduced serum cholesterol by 11% (261.9 mg/dl vs 233.2 mg/dl, P < 0.01) and LDL-C by 22% (191.9 mg/dl vs 149.3 mg/dl, P < 0.01). D-dimer was significantly decreased (0.38 ng/L vs 0.28 ng/L, P = 0.02) and tPA, PAI-1 and fibrinogen tended to decrease after therapy. Fluvastatin therapy improved fibrinolytic profile; the result of this study may in part explain the benefit of HMG-CoA reductase inhibitor on cardiovascular system other than lipid lowering.
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PMID:The effect of fluvastatin on fibrinolytic factors in patients with hypercholesterolemia. 1139 99

To investigate gender differences in conventional, coagulation and fibrinolytic factors in South Asian ischaemic stroke patients, we compared these variables in 50 South Asian females (SAFP) with 90 South Asian males (SAMP) with ischaemic stroke and in 52 females (SAFC) and 38 males (SAMC) without stroke. Plasminogen activator inhibitor-1 (PAI-1) antigen levels were significantly higher in SAFP compared with SAMP (18.2 vs. 13.3 U/ml, P = 0.04) even after adjustment for known covariates, but there was no difference in PAI-1 antigen levels between males and females in the control group. South Asian females exhibited higher levels of factor VII antigen and FVII:C activity in both stroke patients (114 vs. 99% in males, P = 0.01; 116 versus 104% in males, P = 0.04) and controls (116 vs. 97% in males, P = 0.004; 115 vs. 93% in males, P = 0.01). There were no significant differences in the levels of fibrinogen (3.8 vs. 3.7 g/l), FXIIa (2.2 vs. 2.4 ng/ml), von Willebrand factor (1.8 vs. 1.9 IU/ml) and tissue plasminogen activator (11.4 vs. 12.0 ng/ml) in SAMP and SAFP respectively. These results suggest that South Asian females have increased FVII levels and that females with a history of ischaemic stroke have a decreased fibrinolytic potential in comparison with males.
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PMID:Decreased fibrinolytic potential in South Asian women with ischaemic cerebrovascular disease. 1147 61

The effects of tumor necrosis factor (TNF)-alpha on the plasminogen activator (PA)/plasmin system in human dental pulp (HDP) cells were examined. TNF-alpha treatment induced a significantly high level of PA activity in the conditioned medium of HDP cells in a time- and dose-dependent manner, compared with untreated control cells. Western-blot analysis revealed that tissue type (t)PA protein in conditioned medium was increased by TNF-alpha when compared with control medium. Furthermore the tPA mRNA level had increased in HDP cells treated with TNF-alpha, as determined by reverse transcription-polymerase chain reaction, but urokinase PA and PA inhibitor-1 mRNA levels did not increase. We examined the effects of TNF-alpha against activities of matrix metalloproteinases (MMPs) using zymography. TNF-alpha stimulated MMP-2 activity in conditioned medium and stimulated MMP-9 activity with addition of plasminogen into conditioned medium. The present results suggested that TNF-alpha stimulates PA activity via an enhancement of tPA gene expression in HDP cells and MMP-2 activity, and further that tPA-activated TNF-alpha stimulated MMP-9.
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PMID:Stimulation of plasminogen activator activity and matrix metalloproteinases of human dental pulp-derived cells by tumor necrosis factor-alpha. 1148 46

The effect of wound fluids collected from acute well-healing wounds and chronic nonhealing venous leg ulcers on the plasminogen activation system of keratinocyte and fibroblast cell cultures was studied in a simplified wound-healing model. Acute wound fluid was collected from donor sites of split skin grafts at different time points representing the progressive healing of the wound. Urokinase-type plasminogen activator, tissue-type plasminogen activator, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor 1 expression were studied. The methods used were immunocapture assay and immunocytochemistry. The results indicated that the later the acute wound fluid was collected, the greater the urokinase-type plasminogen activator and the lower the plasminogen inhibitor-1 level in treated cells. In contrast, the level of urokinase-type plasminogen activator receptor remained stable irrespective of wound fluid treatment. Immunostaining for urokinase-type plasminogen activator of acute wound fluid-treated cells showed a disseminated punctate pattern over the cell surface, but with chronic wound fluid, urokinase-type plasminogen activator was localized to focal contacts. Our findings support the view that in the acute wound environment the plasminogen activator system is proteolytically active and that in chronic leg ulcers urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor may also be organized for cell adhesion and migration.
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PMID:Differential effects of acute and chronic wound fluids on urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and tissue-type plasminogen activator in cultured human keratinocytes and fibroblasts. 1167 40


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