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)

Plasminogen activators (PA) in the euglobulin fraction of dextran sulfate activated plasma (DS-EF) were assayed on fibrin plates. Activity related to tissue plasminogen activator (t-PA) or urokinase (u-PA) was quantified by antiserum inhibition. The DS-EF contained 30% t-PA, 30% u-PA and 40-50% activity unrelated to t-PA or u-PA. The latter was completely inhibited by 1.7 mumol/1 C1-inhibitor (C1INH), the two former were less sensitive. Addition of flufenamate to the DS-EF (DS-EF/Fluf) from normal and two factor XII (F XII)-deficient plasmas increased their activities to the same high level. More than 50% of the activity was unrelated to t-PA or u-PA, 30-40% was u-PA and 5-10% t-PA related. After addition of fibrinogen to DS-EF/Fluf and clotting with thrombin, the remaining solution contained only about 30% of the total activity, including less than 10% u-PA. The epsilon-aminocaproic acid inhibition pattern obtained with the DS-EF was uniform, and thus different from the biphasic pattern obtained with the low fibrin affinity PA, two-chain urokinase. Thus, both the plasma u-PA and the major unidentified PA in plasma have affinity for fibrin.
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PMID:Assay characteristics and fibrin affinity of plasminogen activators of the intrinsic fibrinolytic system. 242 31

Activity of peritoneal plasminogen activator and its regulation by dextran and other macromolecules that clinically suppress postoperative adhesions was studied. Plasminogen activator activity was assayed by a two-stage globinolytic assay that monitors formation of plasmin, as well as by cleavage of a chromogenic peptide substrate (S-2444) in the presence of aprotinin (Trasylol). Plasminogen activator activity was located on the outer surface of human peritoneum. Incubation of peritoneal tissue with buffer in vitro (conditioning) prompted release of plasminogen activator into the conditioning medium. The released plasminogen activator formed a single band on sodium dodecyl sulfate-gel electrophoresis at an apparent molecular weight of 174,000 and was markedly suppressed by antiserum raised against human melanoma tissue-type plasminogen activator. Nonspecific proteolytic activity did not accumulate in the medium during conditioning. The presence of dextran 80 during conditioning of peritoneum reversibly suppressed tissue-bound plasminogen activator activity and reduced plasminogen activator activity in the spent medium. A similar inhibition of peritoneal plasminogen activator was induced by dextran 500, methyl cellulose, and polyvinylpyrrolidone. Dextran, when added to the medium after conditioning, had no direct inhibitory effect on plasminogen activator activity. Dextran did not induce peritoneal production of inhibitor(s) of trypsin, chymotrypsin, or urokinase. On the basis of these findings, two possible mechanisms for the effect of viscous polymers in the reduction of adhesion formation are proposed. These mechanisms consider the importance of peritoneal tissue-type plasminogen activator for removal of fibrin clots and suggest that polymer coating either prevents the shedding of plasminogen activator into the abdominal cavity or reduces the access of fibrin clots to the serosal surfaces.
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PMID:Effect of viscous macromolecules on peritoneal plasminogen activator activity: a potential mechanism for their ability to reduce postoperative adhesion formation. 245 68

Plasminogen activator inhibitor-2 (PAI-2) can regulate the formation of plasmin by inhibiting urokinase and tissue plasminogen activator. PAI-2 is induced in monocytes and endothelium by inflammatory mediators, and it is made in the placenta during pregnancy. PAI-2 is a member of the serine protease inhibitor gene family, and it is particularly similar to chicken ovalbumin. Like ovalbumin, PAI-2 is secreted without cleavage of a signal peptide. To determine the structure of the PAI-2 gene, two bacteriophage lambda human genomic DNA libraries were screened with PAI-2 cDNA probes. Characterization of three positive clones shows that the human PAI-2 gene spans 16.5 kilobases and has eight exons. The 5'-untranslated sequence of the PAI-2 mRNA is 77 base pairs in length as suggested by primer extension and S1 nuclease mapping. The eukaryotic consensus sequence TATAAAA is found 22 base pairs 5' of the proposed cap site. The PAI-2 gene is on chromosome 18q21-23 as determined by hybridization to flow-sorted chromosomes and by in situ hybridization. There appear to be two common PAI-2 alleles that differ by six nucleotides in exons 1, 4, and 8. The structure of the PAI-2 gene is quite different from that of PAI-1 although these two inhibitors have common target protease specificity. In contrast, the structure of the PAI-2 gene is very similar to that of the chicken ovalbumin gene. When protein sequences are aligned to obtain maximal identity, six of the seven intron positions in the PAI-2 gene are identical to those in the chicken ovalbumin gene. We conclude that PAI-2 is the closest mammalian homologue of avian ovalbumin.
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PMID:Structure of the gene for human plasminogen activator inhibitor-2. The nearest mammalian homologue of chicken ovalbumin. 249 65

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 activators and their inhibitors are thought to play an important role in the regulation of a variety of pathologic processes including inflammation and wound healing. IL-1 is one inflammatory mediator which has been shown to increase release of plasminogen activator (PA) Ag and activity by mesenchymal cells such as chondrocytes and synoviocytes. We have found that rIL-1 beta induces a rapid and significant accumulation of both tissue-and urinary-type plasminogen activator (t-PA and u-PA) mRNA and type 1 and 2 plasminogen activator inhibitor (PAI-1 and PAI-2) mRNA in MRC-5 fetal lung fibroblasts. An SV40 transformed fibroblast cell line, XP12RO, showed an identical response of PAI-1 and t-PA message levels but revealed no change in PAI-2 or u-PA mRNA levels with rIL-1 beta stimulation. Treatment with the transcriptional inhibitor actinomycin D blocked accumulation of t-PA, u-PA, PAI-1, and PAI-2 mRNA, suggesting that RNA synthesis is required for accumulation of all four transcripts. Cycloheximide (CHX) treatment altered the rate of PAI-1 and t-PA mRNA accumulation, but both were able to increase in the absence of protein synthesis. CHX blocked the rIL-1 beta-induced increase in PAI-2 mRNA levels normally observed at 8 h, indicating that protein synthesis is required for this response to IL-1. The increase in u-PA message level was augmented in a synergistic fashion by CHX. These data for PAI-2 and u-PA provide evidence for short-lived proteins which act either to modulate transcription of these genes or regulate mRNA stability. Thus plasminogen activators and their inhibitors are regulated in a positive and complex fashion in the fibroblast by IL-1, suggesting an important role for these molecules and this cell type in the response to inflammation.
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PMID:Modulation of mRNA levels for urinary- and tissue-type plasminogen activator and plasminogen activator inhibitors 1 and 2 in human fibroblasts by interleukin 1. 250 87

When compared to normal weight normolipidemic control subjects, dilute blood clot lysis time was found to be obviously (p less than 0.001) prolonged in hypertriglyceridemic patients without proteinuria and slightly (p less than 0.05) accelerated in hyperlipidemic nephrotic patients in spite of their very high levels of plasma fibrinogen. As a result the ratio plasma fibrinogen (mg/dl) per clot lysis time (minutes) was 1.241 +/- 0.08 (X +/- SEM) in control subjects, 0.574 +/- 0.07 in hypertriglyceridemic patients and 2.69 +/- 0.172 in nephrotic patients. This finding suggesting that a larger amount of fibrin is rather readily dispersed from dilute blood clots of nephrotic patients was associated with higher levels of plasma t-PA:Ag (9.45 ng/ml +/- 1.18 in nephrotic patients versus 5.8 ng/ml +/- 1.23 in controls before venous occlusion and respectively 33.1 ng/ml +/- 3.83 versus 20.3 +/- 3.40 in controls after venous occlusion). Plasminogen activator activity of the euglobulins as assessed by the bovine fibrin-agarose plate was significantly higher in nephrotic patients only after venous occlusion. Plasma samples of nephrotic patients exerted a more potent inhibition of fibrinolysis in a urokinase activated system. This effect was, however, mainly due to the high levels of alpha 2 macroglobulin in nephrotic plasma which apparently have little influence on dilute blood clot lysis time.
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PMID:Tissue-type plasminogen activator (t-PA) and dilute blood clot lysis time in nephrotic patients. 250 97

High physiological concentrations of plasma vasopressin (aVP) when achieved by infusion cause an increase in plasma factor VIII coagulant activity and shortening of the euglobulin clot lysis time (ECLT). To investigate the effects of aVP on components of the fibrinolytic pathway and on thrombin generation, 9 healthy volunteers were infused with saline for 30 min followed by aVP for 1 hour and blood samples taken every 30 min for measurement of aVP, ECLT, tissue-type plasminogen activator (t-PA), t-PA inhibition (tPA-I), plasminogen activator inhibitor 1 (PAI-1 Ag), activated partial thromboplastin time (APTT), fibrinopeptide A (FPA), fibrinopeptide B 15-42 (FPB beta 15-42) and cross-linked fibrin breakdown products (XL-FDP). Plasma aVP rose to a median of 75 pg/ml after 90 min and fell to 13.8 pg/ml 30 min later. The APTT fell from 43.5 to 35 sec (p less than 0.01) but there was no change in plasma FPA or in XL-FDP. Plasminogen activator activity (10(6)/ECLT2) increased from 25 to 736 units (p less than 0.01) and t-PA from 200 to 1012 mIU/ml (p less than 0.01). tPA-I fell from 8.0 to 2.7 IU/ml at 90 min (p less than 0.05) but PAI-1 Ag remained unchanged. Plasma FPB beta 15-42 was 2.4 and 1.2 pmol/ml before infusion with aVP and showed a small rise to 3.5 pmol/ml after 60 min (p less than 0.05). The results show the effects of aVP on fibrinolysis are mediated by an increase in t-PA. In the absence of thrombin generation the rise in t-PA was not accompanied by changes in XL-FDP.
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PMID:Effect of physiological concentrations of vasopressin on components of the fibrinolytic system. 250

Plasminogen activation is catalyzed both by tissue-type-(t-PA) and by urokinase-type plasminogen activator (u-PA). This reaction is controlled by plasminogen activator inhibitor type 1 (PAI-1) that is either present in plasma or bound to fibrin, present in a thrombus. We studied the mechanism of in vitro inhibition of both t-PA and u-PA activity by PAI-1 bound to fibrin. It is shown that activation of latent PAI-1 unmasks a specific fibrin-binding site that is distinct from its reactive site. This reactive site of activated PAI-1 bound to fibrin is fully exposed to form complexes with t-PA and u-PA, that are unable to activate plasminogen. Upon complex formation with either one of the plasminogen activators, PAI-1 apparently undergoes a conformational change and loses its affinity for fibrin. Consequently, complexes of u-PA and PAI-1 dissociate from the fibrin matrix and are encountered in the fluid phase. In contrast, t-PA/PAI-1 complexes remain bound to fibrin. By employing recombinant t-PA deletion-mutant proteins, that precisely lack domains involved in fibrin binding, we demonstrate that binding of t-PA/PAI-1 complexes is mediated by both the "finger" (F) and the "kringle-2" (K2) domain of t-PA. A model is proposed that explains inhibition of the fibrinolytic process, at the level of plasminogen activation by t-PA, directed by PAI-1 bound to fibrin. An implication of the proposed model is that t-PA/PAI-1 complexes and free t-PA compete for the same binding sites on fibrin.
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PMID:Interaction between plasminogen activator inhibitor type 1 (PAI-1) bound to fibrin and either tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). Binding of t-PA/PAI-1 complexes to fibrin mediated by both the finger and the kringle-2 domain of t-PA. 250 41

Plasminogen activator inhibitor (PAI) was purified in active form from porcine platelets under nondenaturing conditions. The purified inhibitor (Mr 47,000) reacts with tissue-type plasminogen activator (t-PA), urokinase (UK), and activated protein C (APC) to yield both SDS-stable complexes and a modified PAI of slightly reduced molecular weight. The second-order rate constants for the inhibition of t-PA and UK by PAI are 3.5 X 10(7) and 3.4 X 10(7) M-1 s-1, respectively. Activated protein C reacts with PAI with a second-order rate constant of 1.1 X 10(4) M-1 s-1. This rate is not accelerated by protein S, phospholipid, and calcium, or heparin. It is concluded that (1) PAI can function as both inhibitor and substrate of its target proteases, (2) if APC promotes fibrinolysis via inactivation of PAI, then APC must be present in concentrations several orders of magnitude greater than t-PA, or the interaction of APC and PAI must be accelerated by presently unknown mechanisms, and (3) in the absence of heparin, platelet PAI is the most rapid inhibitor of APC yet described.
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PMID:Platelet plasminogen activator inhibitor: purification and characterization of interaction with plasminogen activators and activated protein C. 250 42

Study has been made of the influence of addition of human NH2 terminal glutamic acid plasminogen (Glu-Plg) or human NH2 terminal lysine plasminogen (Lys-Plg) to normal citrated plasma upon the rate of lysis of fully crosslinked plasma clots in the presence of single or two chain urokinase type plasminogen activator (scu-PA/tcu-PA) or tissue plasminogen activator (t-PA). The specificity of any thrombolytic property was evaluated by measurement of plasma fibrinogen levels. Lys-Plg added to a concentration of 20% of normal plasma plasminogen caused 5 to 6 fold increase in the extent of lysis observed at 6 hours by 100 units/ml of scu-PA and with a small increase in fibrinogenolysis. Glu-Plg added at 20% of normal level had no influence on thrombolysis but at 50% of normal caused increased thrombolysis with rapid depletion of plasma fibrinogen. An apparently synergistic effect of addition of tcu-PA on scu-PA activity was increased by addition of plasminogen (e.g. addition of 20% Lys-Plg increased the lysis rate 4 to 5 fold over the first hour equivalent to an increase of potency of approximately three to four fold). Addition of plasminogen up to double the normal plasma concentration was observed to have no influence on clot lysis in the presence of t-PA. Plasminogen potentiated the rate of lysis by scu-PA/t-PA synergic mixtures with an approximately 1.5 to 1.9 fold increase in potency. Potentiation occurred without increase in the depletion of plasma fibrinogen.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potentiation by Lys-plasminogen of clot lysis by single or two chain urokinase-type plasminogen activator or tissue-type plasminogen activator. 250 59


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