Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.68 (tissue plasminogen activator)
11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms leading to reduction of peritoneal fibrinolytic activity in conditions that are associated with the formation of intra-abdominal adhesions were studied. Tissue plasminogen activator was found, by antibody inhibition techniques, to be the activator of fibrinolysis in homogenates of control peritoneum (n = 6). Homogenates of control (n = 10) and inflamed peritoneum (n = 10) were analysed. Plasminogen activating activity was much lower in inflamed peritoneum (median 0.07 IU/cm2) than in control tissue (median 12.0 IU/cm2) (p less than 0.001). Levels of tissue plasminogen activator and alpha 2-antiplasmin were similar in both control and inflamed tissue. Plasminogen activator inhibitor-1, not detectable in control peritoneum, was present in inflamed tissue and might be the reason for the reduction in functional fibrinolytic activity.
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PMID:Peritoneal fibrinolytic activity and intra-abdominal adhesions. 197 64

The ability of tissue plasminogen activator (tPA) to induce human umbilical vein endothelial (HUVE) cell migration was studied using an in vitro, serum-free wound assay system. At pharmacological doses, tPA stimulated HUVE cell migration dose-dependently. Treatment of cells with epsilon amino caproic acid (EACA) to detach cell-surface and extracellular matrix bound plasminogen, which could lead to plasmin generation, resulted in increased HUVEcell migration on stimulation with tPA.Plasminogen activator inhibitor-1 (PAI-1), a natural plasminogen activator inhibitor, abolished tPA-induced HUVEcell migration. These results demonstrate for the first time that tPA is capable of stimulating endothelial cell migration in wound assays and this effect is susceptible to PAI-1 inhibition.
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PMID:Tissue-plasminogen activator stimulates endothelial cell migration in wound assays. 212 Nov 40

Although the mechanisms involved in the pathophysiology of primary pulmonary hypertension have not yet been delineated, thrombosis has been implicated. This study was designed to determine whether thrombin activity as reflected by plasma concentrations of fibrinopeptide A (FPA), a marker of the action of thrombin on fibrinogen, is increased in patients with primary pulmonary hypertension. To evaluate fibrinolytic activity, we measured plasma concentrations of tissue-type plasminogen activator, plasminogen activator inhibitor-1, and cross-linked fibrin degradation products. We studied 31 patients with primary pulmonary hypertension. Plasma FPA concentrations measured by radioimmunoassay, were elevated to 87.4 +/- 36.9 ng/ml (mean +/- SEM). Fifteen minutes after administration of heparin (5,000 U), FPA concentrations decreased to 6.8 +/- 1.4 ng/ml (p less than 0.001 compared with preheparin levels). In 21 of 30 patients (70%), FPA concentrations after heparin administration were less than half the preheparin levels, a response consistent with inhibition of thrombin by heparin and the short half-life of FPA. Despite evidence for marked thrombin activity, plasma concentrations of cross-linked fibrin degradation products were normal in all but four patients. Plasminogen activator inhibitor-1 activity was elevated in 19 of the 27 patients in whom it was measured, potentially limiting the fibrinolytic response. The elevations of FPA indicate that thrombin activity is increased in vivo in patients with primary pulmonary hypertension. Thus, sequential assays of plasma markers of thrombosis and fibrinolysis in vivo may help identify those patients who may benefit from treatment with anticoagulants.
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PMID:Fibrinopeptide A levels indicative of pulmonary vascular thrombosis in patients with primary pulmonary hypertension. 239 5

To evaluate the effect of endotoxin on the fibrinolytic response, we administered Escherichia coli endotoxin (4 ng per kilogram of body weight) intravenously to 19 healthy volunteers and measured fibrinolytic proteins, protease inhibitors, neutrophil elastase, and von Willebrand factor in serial blood samples obtained over 24 hours. One hour after endotoxin administration, the level of tissue plasminogen activator (t-PA) antigen rose from 10 to 23 ng per milliliter, peaking at 52 ng per milliliter at three hours. The level of alpha 2-plasmin inhibitor-plasmin complexes increased sevenfold, peaking at three hours. Plasminogen-activator inhibitor-1 activity rose more slowly, from 7 U per milliliter to a maximum of 49 U per milliliter at five hours. The concentrations of neutrophil elastase and von Willebrand antigen were unchanged at one hour, increased approximately threefold by 3 hours, and remained elevated at 24 hours. None of these measures changed in a control group (n = 5) given intravenous saline instead of endotoxin. We studied t-PA functional activity in four subjects. The level of activity rose rapidly, from 1.2 ng per milliliter at base line to 8.3 ng per milliliter at one hour and 13.9 ng per milliliter at two hours; it was undetectable at three hours. This increase in plasminogen activator activity was abolished in vitro by incubation of t-PA with an antiserum specific for human t-PA, suggesting that t-PA may be directly responsible for plasmin generation in the response to endotoxin. We conclude from this study of healthy subjects that endotoxin activates the fibrinolytic system, beginning with release of t-PA in the blood within one hour. The early activation of plasmin by endotoxin may prevent thrombosis, and the increase in fibrinolysis is then offset by the release of plasminogen activator inhibitor.
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PMID:Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. 278 17

Plasminogen activator inhibitor-1 (PAI-1) is a specific and rapid inhibitor of tissue plasminogen activator (tPA) and urokinase. Clinical studies suggest that PAI-1 may play a crucial role in the regulation of fibrinolysis. A number of factors modulate PAI-1 activity in endothelial cell culture, and the isolation of PAI-1 cDNA now allows study of PAI-1 regulation at the mRNA level. We examined the effect of endothelial cell growth factor (ECGF) and heparin on PAI-1 expression in human umbilical vein endothelial cell (HUVEC) culture. The addition of ECGF and heparin to HUVEC cultures results in a 3-10-fold decrease in the PAI-1 activity secreted into the conditioned media. This effect is mediated at the mRNA level. A decrease in PAI-1 is also seen with higher concentrations of ECGF alone, but is greatly enhanced by the addition of heparin. No significant change in tPA antigen or mRNA levels was observed.
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PMID:The addition of endothelial cell growth factor and heparin to human umbilical vein endothelial cell cultures decreases plasminogen activator inhibitor-1 expression. 313 92

Endothelial cells were isolated from arteries and veins obtained from elderly people at autopsy and propagated for 37 to 69 population doublings. The cells secreted tissue-type plasminogen activator (t-PA) and PA inhibitor-1, and, after subculturing, urokinase-type PA (u-PA) antigen. The following differences between endothelial cells from adult arteries and veins were observed: 1) The cells had the potential to be propagated as a healthy monolayer. The diameter of aortic endothelial cells increased after 8 to 19 population doublings, while a homogeneous population of small diameter vena cava cells was retained for 35 population doublings. 2) The amount of secreted t-PA varied. Vena cava cells produced four times more t-PA than aorta cells, and 20-fold more than umbilical artery or vein endothelial cells. The t-PA mRNA content of vena cava cells did not exceed that of aorta cells, but was fourfold greater than that of umbilical cord endothelial cells. 3) The release of u-PA antigen varied. No u-PA antigen was detectable in conditioned medium of primary cultures of human aorta and vena cava endothelial cells or of early passage vena cava cells. After prolonged subculturing, vena cava cells started to secrete u-PA. Endothelial cells from aorta and other adult arteries, however, started secreting u-PA after one to four passages, parallel to the occurrence of enlarged endothelial cells. u-PA was present as a u-PA/inhibitor complex and as a single-chain u-PA. These differences may be developmentally related to their artery or vein origin or may reflect differences acquired during the "life history" of these blood vessels in vivo. Our data suggest that the release of u-PA antigen by human macrovascular endothelial cells can be used as an indicator of cell senescence.
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PMID:Production of plasminogen activators and inhibitor by serially propagated endothelial cells from adult human blood vessels. 330 Jun 18

Human foreskin microvascular endothelial cells synthesize and release tissue-type plasminogen activator (t-PA) in similar amounts as do endothelial cells from umbilical cord artery and vein. Human thrombin increases the production of t-PA by these cells, which could be visualized from 8 h after addition of 0.1-5 units/ml thrombin by fibrin autography after SDS polyacrylamide gel electrophoresis of the endothelial cell conditioned media. Thrombin also increased the secretion of t-PA antigen. Together with t-PA, human microvascular cells release urokinase-type plasminogen activator (u-PA) antigen and endothelial cell-type PA inhibitor, PA inhibitor-1, which were both demonstrated by specific immunoprecipitation from radiolabeled endothelial cell conditioned medium. Thrombin increases the release of u-PA antigen, but no u-PA activity could be demonstrated. Thrombin induced a two-fold stimulation of the synthesis and secretion of PA inhibitor-1 antigen. At 0.1 unit/ml thrombin also an increase in PA inhibitor activity was found. At high concentrations of thrombin a decrease of PA inhibitor activity was found, due to the conversion of the active 46 kD PA inhibitor-1 into a 42 kD product without PA inhibitor activity. Our data indicate that interaction of thrombin with microvascular endothelial cells will shift the balance between t-PA, u-PA and PA inhibitor-1, and thus affects the regulation of fibrinolysis.
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PMID:Effect of thrombin on the production of plasminogen activators and PA inhibitor-1 by human foreskin microvascular endothelial cells. 349 79

Plasminogen activator inhibitor-1 (PAI-1), an important risk factor for thrombotic diseases, is a member of the superfamily of serine proteinase inhibitors. To define structural rearrangements occurring during interaction between PAI-1 and its target proteinases we have raised monoclonal antibodies against the PAI-1/t-PA complex. Thirteen out of 401 monoclonal antibodies reacted preferentially with the PAI-1/t-PA complex as compared to free PAI-1 or free t-PA. Detailed characterization revealed the presence of two non-overlapping neoantigenic epitopes in the PAI-1/t-PA complex. Both neoantigenic epitopes were also exposed after complex formation between PAI-1 and either urokinase-type plasminogen activator, plasmin or thrombin as well as after cleavage of the reactive site loop of non-inhibitory substrate type PAI-1 variants. Thus, we have identified two neoantigenic epitopes, localized entirely in PAI-1, and commonly exposed after complex formation of active PAI-1 with various proteinases or after cleavage of substrate PAI-1. These monoclonal antibodies should facilitate further studies on the mechanism of interaction between various PAI-1 forms and its target proteinases.
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PMID:Characterization of common neoantigenic epitopes generated in plasminogen activator inhibitor-1 after cleavage of the reactive center loop or after complex formation with various serine proteinases. 749 51

Plasminogen activator inhibitor-1 (PAI-1) is a primary endogenous inhibitor of tissue-type plasminogen activator (t-PA). In this study, we examined the effects of oversulfated fucoidan (OSF) derivatives and heparin on lipopolysaccharide (LPS)-induced release of PAI-1 antigen from cultured human umbilical vein endothelial cells (HUVEC). Addition of LPS (10 micrograms/ml) enhanced the release of PAI-1 by HUVEC but not of t-PA antigen. At 18 h, a 2.4-fold increase in the extracellular PAI-1 level was observed. The increased PAI-1 level was reduced to control level by the simultaneous addition of 10 micrograms/ml of OSF or heparin. The suppressive effect of native fucoidan was negligible. We also examined the molecular size effect of OSF, using 10-20, 20-40, and 40-60 kDa fragments. The result indicated that these fragments were effective as well as the 100-130 kDa form of OSF, hence suggesting an important role of the degree of sulfation. Interleukin-1 beta (IL-1 beta) is a potent inducer of PAI-1 in cultured HUVEC. Heparin, OSF, and its fragments did not suppress the IL-1 beta-induced release of PAI-1 antigen. Treatment of HUVEC with heparitinase or monoclonal antibody against heparin sulfate proteoglycan (HSPG) resulted in a complete loss of its ability to enhance PAI-1 release in response to LPS stimulation, while the chondroitinase ABC treatment hardly affected the PAI-1 production. These results suggest that HSPG is involved in the initial binding of LPS to HUVEC. The suppressive effects of OSF and heparin on LPS-induced PAI-1 release may result from the inhibition of LPS binding to the cell surface HSPG.
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PMID:Oversulfated fucoidan and heparin suppress endotoxin induction of plasminogen activator inhibitor-1 in cultured human endothelial cells: their possible mechanism of action. 757 76

Ischemic electrocardiographic changes were recorded within 2 hours of admission using a 12-lead electrocardiographic continuous monitor with a 20-second scanning interval and an alarm mode for asymptomatic events. Blood samples were obtained at admission and at the moment of asymptomatic events (group A). In the other patients who did not develop ischemia, a second blood sample was taken 12 hours later (group B). We determined prothrombin time, activated partial thromboplastin time, clotting factor VIII activity, tissue plasminogen activator activity, tissue plasminogen activator inhibitor-1, cross-linked fibrin degradation product, and thrombin-antithrombin III complexes. There was a statistically significant difference between group A and B patients when the basal samples were analyzed for thrombin-antithrombin III (p = 0.046) and d-Dimer (p = 0.005). Prothrombin fragment 1 + 2 were significantly reduced, and d-Dimer was elevated when basal blood samples were compared with the second sample in patients who developed silent events (p = 0.008 and 0.055, respectively). A plasma concentration of thrombin-antithrombin III complex was also significantly decreased when sample 2 was compared with the basal blood sample (p = 0.039). Five recurrent episodes of angina and 2 nonfatal infarctions occurred, and 4 urgent revascularization procedures were performed in group A. In group B, there was only 1 nonfatal infarction (p = 0.01). The results of the present study suggest that a time-dependent thrombotic process is detectable in the blood stream as a cyclic movement. Further studies are needed to determine if some other factors, such as intensive shear stress in the vessel wall, may activate plaque instability during asymptomatic episodes.
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PMID:Time significance of acute thrombotic reactant markers in patients with and without silent myocardial ischemia and overt unstable angina pectoris. 761 Nov 44


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