Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interaction of tissue plasminogen activator derived from a melanoma cell line with a specific plasminogen activator inhibitor from placental tissue, which inhibits urokinase and tissue plasminogen activator but not plasmin, was studied. Tissue plasminogen activator exists in two forms, a one chain and a two chain molecule. It was found that the two enzyme species each form 1:1 complexes with the inhibitor and that the two chain enzyme binds the inhibitor very strongly, Ki = 3 X 10(-10) mol/l, whereas the one chain enzyme forms a much weaker complex, Ki is approximately 10(-7) to 10(-8) mol/l. Substrate hydrolysis is much more efficiently catalysed by the two chain plasminogen activator than by the one chain activator.
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PMID:Different inhibition of one and two chain tissue plasminogen activator by a placental inhibitor studied with two tripeptide-p-nitroanilide substrates. 293 Aug 96

Alteplase is a human tissue plasminogen activator (t-PA) produced by recombinant DNA technology. It is a relatively fibrin-specific thrombolytic agent, used primarily to lyse coronary artery clots. It has proven effective in the treatment of acute myocardial infarction (AMI). Despite continuous reevaluation of pharmacokinetic parameters for t-PA, limited distribution and clearance data mandate administration of t-PA as a continuous infusion. Tissue plasminogen activator is eliminated primarily by hepatic metabolism with an elimination half-life of five to ten minutes. Plasma levels show great interindividual variation but correlate with infusion rate and decrease in fibrinogen level. The current recommended dose is 100 mg administered as a 10-mg iv bolus followed by a continuous infusion over three hours. However, 40-150 mg has been used in clinical trials. The compound has undergone extensive testing, comparing it with placebo and streptokinase (SK), and combining it with angioplasty and coronary artery bypass surgery. Tissue plasminogen activator is effective at opening clotted coronary arteries in approximately 70 percent of AMI patients and has been shown to be approximately twice as effective as SK in one U.S. trial. Although there is considerable evidence of efficacy with t-PA, data evaluating the influence of t-PA on mortality are limited, but suggest a reduction to five percent. Currently, thrombolytic therapy is indicated for patients experiencing a transmural AMI with onset of symptoms within three to six hours before presenting to the emergency room. Active internal bleeding or conditions predisposing to serious hemorrhage are contraindications to thrombolytic therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alteplase: a tissue plasminogen activator for acute myocardial infarction. 312 86

Tissue plasminogen activator (tPA) was covalently linked by disulfide bonds to a monoclonal antibody specific for the amino terminus of the beta chain of fibrin (antibody 59D8). The activity of the tPA-59D8 conjugate was compared with that of tPA, urokinase (UK), and a UK-59D8 conjugate. For lysis of fibrin monomer, tPA was 10 times as potent as UK, whereas both UK-59D8 and tPA-59D8 conjugates were 100 times as potent as UK and 10 times as potent as tPA. Conjugation of tPA or UK to antibody 59D8 produced a 3.2-4.5-fold enhancement in clot lysis in human plasma over that of the respective unconjugated plasminogen activator. However, the UK-59D8 conjugate was only as potent as tPA alone. Antibody-conjugated tPA or UK consumed less fibrinogen, alpha 2-antiplasmin, and plasminogen than did the unconjugated activators, at equipotent fibrinolytic concentrations. Antibody targeting thus appears to increase the concentration of tPA in the vicinity of a fibrin deposit, which thereby leads to enhanced fibrinolysis.
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PMID:Conjugation to an antifibrin monoclonal antibody enhances the fibrinolytic potency of tissue plasminogen activator in vitro. 313 94

Various human malignant tumors, including malignant melanoma, showed an absence of fibrinolytic activity by the histochemical fibrin slide method. In contrast, a tissue plasminogen activator has been isolated both from extracts of melanoma tissues and melanoma cell lines in culture, and has been characterized to be a potent plasminogen activator. In an attempt to resolve this apparent discrepancy, we studied biopsied specimens of melanoma and several melanoma cell lines by the immunoperoxidase method. Tissue plasminogen activator was observed in melanoma tissues and cell lines while the various inhibitors of fibrinolysis, including alpha 2-anti-plasmin, alpha 2-macroglobulin, alpha 1-antitrypsin, and antithrombin III were found intracellularly only in the melanoma tumor cells, but not in melanoma cell lines. We believe that these inhibitors are derived from the blood and are bound to the tissue plasminogen activator within the melanoma cells. This hypothesis is supported by in vivo studies showing binding of tissue plasminogen activator in cultured cell lines to several inhibitors. Since these are potent inhibitors of fibrinolysis, their presence in tumor cells would explain the lack of fibrinolytic activity in melanoma tissues.
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PMID:Tumor growth and metastases in malignant disease. A review. 314 46

Various human malignant tumors including malignant melanoma showed an absence of fibrinolytic activity in previous histochemical fibrin studies. In contrast, a tissue plasminogen activator has been isolated both from extracts of melanoma tissues and melanoma cell lines in culture and has been characterized to be a potent plasminogen activator. In an attempt to resolve this apparent discrepancy, we studied biopsies specimens of melanoma, several melanoma cell lines and melanoma xenografts by the immunoperoxidase method. Tissue plasminogen activator was observed in melanoma tissues, cell lines and xenografts, while various inhibitors of fibrinolysis, including alpha 2-antiplasmin, alpha 2-macroglobulin, alpha 1-antitrypsin and antithrombin III, were found intracellularly only in the melanoma tumor cells but not in melanoma cell lines nor in xenografts. We believe that these inhibitors are derived from the blood and are bound to the tissue plasminogen activator within the melanoma cells. Their presence in tumor cells would explain the lack of fibrinolytic activity in melanoma tissues.
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PMID:Tissue plasminogen activator and inhibitors of fibrinolysis in malignant melanoma. 314 30

To evaluate functional recovery in 20 consecutive patients with acute myocardial infarction who received recombinant tissue-type plasminogen activator, serial two-dimensional echocardiograms were performed before and immediately after tissue plasminogen activator administration and at 1 and 10 days postinfarction. Tissue plasminogen activator was administered intravenously (17 patients) or by intracoronary infusion (3 patients) after angiographic confirmation of total occlusion. Reperfusion, documented by angiography, occurred in 13 of the 20 patients. The mean time from onset of chest pain to thrombolysis was 5.1 +/- 1.1 hours. Echocardiograms were evaluated for regional function with a visual semiquantitative scoring system by two independent observers who had no knowledge of patient identity, temporal sequence, therapy or effect of therapy. There was no immediate or 24 hour improvement in wall motion. At day 10 compared with pretreatment, 28 of 33 reperfused infarct zone segments versus 6 of 20 nonreperfused infarct segments demonstrated improved wall motion (p = 0.01). This improvement did not relate to time from onset of chest pain to successful thrombolysis. Of reperfused infarct zone segments in the distribution of coronary artery balloon dilation, 19 of 23 segments exhibited improvement versus 7 of 17 (reperfused, no angioplasty) and 6 of 20 (nonreperfused, no angioplasty) segments (p = 0.001). Infarct zone segments reperfused at the time of ongoing chest pain demonstrated functional recovery compared with segments reperfused in the absence of chest pain (18 of 23 versus 10 of 20, respectively; p = 0.05). Thus, in this uncontrolled series, there was echocardiographically detectable improvement in function of reperfused infarct segments 10 days after coronary thrombolysis with recombinant tissue plasminogen activator.
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PMID:Regional wall motion improvement after coronary thrombolysis with recombinant tissue plasminogen activator: importance of coronary angioplasty. 316 Jul 57

The effects from alterations in inspired oxygen tension on the fibrinolytic activity in vessel walls was studied in rats. Tissue plasminogen activator activity was measured semiquantitatively with the histochemical technique. During severe hypoxic conditions (FIO2 = 0.05) the fibrinolytic activity in the aorta was significantly reduced as compared to control animals. At 24 hours with slightly higher oxygen tension (FIO2 = 0.08) the activity was increased. When breathing pure oxygen (FIO2 = 1.0) the fibrinolytic activity was increased in the aorta after 8 hours. Following chronic hypoxia for 6 weeks (FIO2 = 0.1) the activity in the caval vein was increased. Changes in inspired oxygen tension thus affected the endothelial cells and changed their expression of plasminogen activator activity.
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PMID:Modulation of tissue fibrinolysis from hypoxia and hyperoxia. 403 52

Tissue plasminogen activator purified from human uterine tissue exhibits differences in N-terminal starting positions in relation to the melanoma cell plasminogen activator usually studied. A new starting position is compatible with an additional N-terminal processing apart from those already known. Like the melanoma activator, the uterine activator was found to yield protein chains starting at either of two positions. One of these was identical between uterine and melanoma activators, whereas the other was unique in each case. The most abundant starting position for the uterine preparation was at a valine residue, apparently from cleavage of a Gln-Val bond, and corresponding to Val-7 of the longest form of the melanoma activator chain.
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PMID:Differences between uterine and melanoma forms of tissue plasminogen activator. 653 14

Tissue plasminogen activator (t-PA) in plasma was separated from inhibitors by adsorption on lysine-Sepharose. It was then determined indirectly by measuring the plasmin generated from plasminogen with poly-lysine as stimulator, in a chromogenic, parabolic rate assay. The reaction proceeded with tissue plasminogen activator and plasmin(ogen) adsorbed on the gel, and followed the kinetics described for similar parabolic rate assays in soluble systems. The assay was standardized against melanoma plasminogen activator (m-PA) and had the sensitivity range of 0.001-0.020 IU (4-80 pg). Anti-m-PA IgG quenched the activity generated in plasma on venous occlusion and part of the activity in pre-occlusion plasma. The method was sensitive to purified urokinase. The basic plasma values in resting normal individuals were: mean 0.08, range 0.01-0.26 X 10(3) IU/l (n = 19), and after 20 min of venous occlusion: mean 2.48, range 0.24-4.34 X 10(3) IU/l (n = 10). The assay correlates well with a fibrin plate method, r = 0.96.
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PMID:A sensitive assay for tissue plasminogen activator activity in plasma, using adsorption on lysine-sepharose. 654 74

Herpes simplex virus (HSV) infection is histopathologically associated with vascular injury, fibrinoid necrosis and inflammatory cell infiltrates. We have previously shown in vitro that HSV infection of human umbilical vein endothelial cells (HUVEC) promotes a procoagulant phenotype manifest by the induction of tissue factor, the loss of thrombomodulin, and an increase in platelet adhesion. In these studies we examined the effects of HSV infection on HUVEC plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA). HSV infection caused the loss of PAI-1 in the extracellular matrix (ECM) and that released into the supernatant of HUVEC. Both activity and antigen levels of the Serpin inhibitor are diminished as a result of HSV infection. The loss of inhibitor is not secondary to diminished vitronectin (Vn), the primary binding protein of PAI-1 in the ECM, but appears to be secondary to decreased synthesis at the RNA level. Tissue plasminogen activator (t-PA) synthesis is also decreased in endothelial HSV infection. PAI-1 loss may further promote a procoagulant phenotype in HSV infection in vivo.
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PMID:Herpes simplex virus decreases endothelial cell plasminogen activator inhibitor. 768 40


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