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)

In a rabbit jugular vein thrombosis model, the thrombolytic properties of melanoma tissue-type plasminogen activator (mt-PA), recombinant t-PA (rt-PA), and a t-PA mutant that lacked the growth factor- and kringle one-domain (designated FK2P, as it contained the finger-, kringle two-, and protease-domain) were compared. Over the dose range tested (3.75 to 30 nmol/kg) a similar, dose-dependent, thrombolytic efficacy was found for the 3 enzymes when given as bolus injections. When given as a 90-min infusion, FK2P was superior to rt-PA at the tested dose of 15 nmol/kg. The effects on systemic plasma fibrinogen, plasminogen and alpha 2-antiplasmin consumption were much larger for rt-PA and FK2P than for mt-PA. The analogue FK2P was cleared more slowly than mt-PA or rt-PA, despite a similar initial alpha half-life: the mean residence time of FK2P was about 10 times as large as that of mt-PA or rt-PA. A comparison with data obtained in vitro suggested that in vivo thrombolytic performance cannot easily be predicted from in vitro data. The efficacy of a thrombolytic agent will also depend on its clearance rate, and may also, within a chosen model, depend on the way it is administered.
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PMID:Thrombolytic properties in a rabbit jugular vein thrombosis model of a tissue-type plasminogen activator mutant lacking the growth factor--and kringle one-domains. 149 99

Fetal basal ganglia astrocytes and C6 glioma cells were plated on the surface of 1.5 cm thick hydrated collagen I wafers. Both cell types migrated through the entire thickness of the wafer within 1 day after plating. The collagen in the wafer was digested and the fine collagen I fibrils were clumped into large strands. By 2-3 days, the collagen strands were digested from the wafers and replaced by a mass of fetal astrocytes or C6 cells joined by their processes. The collagen I digestion and cell migration suggested protease production. In a second series of experiments, cultured C6 cells and E14 fetal astrocytes were immunohistochemically stained for the presence of plasminogen activators as an index of protease production. Both tissue (tPA) and urokinase (uPA) types were observed. Fetal astrocytes and C6 cells were also positive for guanidinobenzoatase, a serine protease associated with migrating cells. These data demonstrate that rapid migration of the cells on and through collagen I fibrils is concomitant with expression of plasminogen activators and proteases which can either activate or function as collagenases and release the cells from the substrate.
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PMID:Mechanisms of C6 glioma cell and fetal astrocyte migration into hydrated collagen I gels. 149 72

Tissue-type plasminogen activator and urokinase are serine proteases secreted by many cell types that participate in biological processes, such as tissue restructuring, cell migration, and tumor metastasis. Clinically, these proteases are used to dissolve coronary fibrin clots that are the proximal causes of acute myocardial infarction. In vivo, the activity of these enzymes is controlled by plasminogen-activator inhibitors, members of the serpin family of protease inhibitors. This study shows that tissue-type plasminogen activator-inhibitor complexes bind in solution to low density lipoprotein receptor-related protein (LRP), a large heterodimeric ubiquitous membrane receptor. In cultured cells, endocytosis and degradation of these complexes is reduced by polyclonal antibodies directed against LRP and inhibited by a M(r) 39,000 protein that binds to LRP and inhibits its interaction with previously known ligands, including apolipoprotein E and alpha 2-macroglobulin. We propose a role for LRP in the clearance of plasminogen activator-inhibitor complexes that is analogous to its function in the endocytosis of alpha 2-macroglobulin-protease complexes.
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PMID:Complexes of tissue-type plasminogen activator and its serpin inhibitor plasminogen-activator inhibitor type 1 are internalized by means of the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. 150 53

1. Intracarotid (i.c.) administration of thrombin induced a marked accumulation of 111indium-labelled platelets and 125I-labelled fibrinogen within the cranial vasculature of anaesthetized rabbits. 2. Thrombin (100 iu kg-1, i.c.) - induced platelet accumulation was completely abolished by pretreatment with desulphatohirudin (CGP 39393; 1 mg kg-1 i.c., 1 min prior to thrombin). Administration of CGP 39393 1 or 20 min after thrombin produced a significant reduction in platelet accumulation. 3. Intravenous (i.v.) administration of the platelet activating factor (PAF) receptor antagonist BN 52021 (10 mg kg-1) 5 min prior to thrombin (100 iu kg-1, i.c.) had no effect on platelet accumulation. 4. An inhibitor of NO biosynthesis, L-NG-nitro arginine methyl ester (L-NAME; 100 mg kg-1, i.c.), had no significant effect on the cranial platelet accumulation response to thrombin (10 iu kg-1, i.c.) when administered 5 min prior to thrombin. 5. Defibrotide (32 or 64 mg kg-1 bolus i.c. followed by 32 or 64 mg kg-1 h-1, i.c., infusion for 45 min) treatment begun 20 min after thrombin (100 iu kg-1, i.c.) did not significantly modify the cranial platelet accumulation response. 6. Cranial platelet accumulation induced by thrombin (100 iu kg-1, i.c.) was significantly reversed by the fibrinolytic drugs urokinase (20 iu kg-1, i.c., infusion for 45 min), anisoylated plasminogen streptokinase activator complex (APSAC) (200 micrograms kg-1, i.v. bolus) or recombinant tissue plasminogen activator (rt-PA; 100 micrograms kg-1, i.c. bolus followed by 20 micrograms kg-1 min-1, i.c., infusion for 45 min) administered 20 min after thrombin.8. These results suggest that neither endogenous PAF nor NO modulate thrombin-induced intracranial platelet accumulation in the rabbit. However, fibrin deposition appears to play an important role as shown by the ability of fibrinolytic agents to reverse platelet and fibrinogen accumulation induced by i.c. thrombin.
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PMID:The pharmacological modulation of thrombin-induced cerebral thromboembolism in the rabbit. 150 22

Serum-free conditioned medium (CM) generated by human umbilical vein endothelial cell monolayers following pretreatment with 100 ng/ml of phorbol myristate acetate (PMA) promoted human polymorphonuclear leukocyte (PMNL) migration as assayed in blindwell chambers. Stimulation of PMNL migration in response to CM was dependent on the dose of PMA used to pretreat the endothelial cells as well as the duration of incubation time to generate CM. Phorbol esters have been previously shown to release plasminogen activators from vascular endothelial cells. In the present study, pretreatment of endothelial cells with PMA also increased plasminogen activator activity in CM at a time course similar to the generation of PMNL chemoattractant activity. Treatment of CM with a polyclonal antibody against human urokinase-type plasminogen activator (uPA) not only inhibited uPA activity, but also significantly reduced PMNL chemoattractant activity when compared with untreated CM. In contrast, treatment of CM with an antibody directed against tissue-type plasminogen activator (tPA) did not affect PMNL migratory activity. Furthermore, when CM was passed over an anti-uPA immunoaffinity column, plasminogen activator activity was reduced 90% and chemoattractant activities was reduced 68%. Both plasminogen activator and chemoattractant activities were reconstituted in the eluate from the anti-uPA column. These data demonstrate that uPA present in the CM from PMA-pretreated endothelial cells stimulates PMNL chemoattractant activity and suggests a possible role for endothelial cell-derived uPA in stimulating migration of peripheral blood leukocytes at an inflammatory locus.
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PMID:Urokinase in conditioned medium from phorbol ester-pretreated endothelial cells promotes polymorphonuclear leukocyte migration. 151 9

This study was conducted to compare the thrombolytic effect of a novel modified tissue plasminogen activator, E6010, with that of recombinant human tissue plasminogen activator (t-PA), administered by single intravenous bolus injection in pigs with occlusive coronary thrombosis. Thrombosis was induced by electrical stimulation of the intimal surface of the left circumflex coronary artery. Coronary blood flow velocity and hemodynamic parameters were observed for 1 hr after complete cessation of coronary flow. Ten minutes after heparin injection (300 U/kg), E6010, t-PA or placebo was intravenously administered as a bolus. E6010 at 0.2 and 0.4 mg/kg caused recanalization of the occluded coronary artery in 1 of 6 and 5 of 5 pigs, respectively. The time to recanalization after 0.4 mg/kg of E6010 was 22 +/- 11 min (mean +/- S.E.M.). t-PA (0.4 mg/kg) caused recanalization in only 1 of 5 pigs. Recanalization did not occur in any of the 6 animals administered placebo. Plasma clearance of E6010 was smaller than that of t-PA (4.9 +/- 0.3 vs. 9.4 +/- 3.8 ml/min/kg). There were no significant differences in plasma levels of fibrinogen, alpha 2-plasmin inhibitor and plasminogen among the placebo, E6010 and t-PA groups. These results suggest that the slower clearance of E6010 from plasma contributes to the effective thrombolytic action of E6010 following single intravenous bolus injection.
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PMID:Thrombolytic effects of a novel modified tissue plasminogen activator, E6010, on coronary thrombosis in the pig. 151 78

Tissue-type plasminogen activator, von Willebrand factor, and plasminogen-activator inhibitor type 1 plasma levels were measured at first consultation in 85 consecutive patients infected with human immunodeficiency virus. Patients were assigned to three groups according to clinical status: mild disease group, intermediate group, and acquired immunodeficiency syndrome group. Significant differences were found in von Willebrand factor, tissue-type plasminogen activator, and plasminogen-activator inhibitor type 1 plasma levels among the three groups: severe clinical status was associated with higher von Willebrand factor, tissue-type plasminogen activator, and plasminogen-activator inhibitor type 1 plasma levels. Significant correlations were found among these three parameters, such known biologic prognostic indicators of human immunodeficiency virus infection as IgA, anti-p24 antibodies, p24 antigenemia, CD4+ lymphocytes, beta 2-microglobulin, and the clinical status. The prognostic relevance of plasma von Willebrand factor and tissue-type plasminogen activator levels at the time of entry into the study was then investigated in a cohort of 65 of the 85 patients who had follow-up during a median period of 22 months. The median survival time for all patients was 39 months after the first consultation. A plasma von Willebrand factor level greater than 200% of the control value had a positive predictive value of 86% for determining nonsurvivors; the median survival time for such patients was 9 months after the first consultation. A positive predictive value of 100% in recognizing nonsurvivors was found for tissue-type plasminogen factor plasma levels greater than 20 ng/ml; the median survival time for these patients was 2 months after the first consultation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:von Willebrand factor antigen, tissue-type plasminogen activator antigen, and risk of death in human immunodeficiency virus 1-related clinical disease: independent prognostic relevance of tissue-type plasminogen activator. 151 88

Using a biochemical technique, the authors characterized and identified a plasminogen activator (PA) derived from tissue extracts of antrochoanal polyp (AP) and paranasal mucous membrane (PMM) with chronic sinusitis. The results of fibrin zymography indicated that the tissue extracts of AP revealed two lytic zones and that those of PMM revealed a single lytic zone on fibrin-agarose plates. One of the AP zones exhibited the same relative mobility as the PMM zone (molecular weight: 65 kd), while the other AP zone had a smaller molecular weight (about 54 kd). Goat immunoglobulin G (IgG) fraction of antihuman uterine tissue-type plasminogen activator (t-PA) inhibited the 65-kd lytic zones of AP and PMM. Antihuman low-molecular-weight urokinase inhibited only the 54-kd lytic zone of AP, and nonspecific goat IgG failed to inhibit any of the lytic zones. On the other hand, 10(-2) mol trans 4-(aminomethyl)cyclohexane-carboxylic acid (t-AMCHA) inhibited all of the lytic zones. No lytic zones could be observed on plasminogen-free fibrin-agarose plates. These findings confirmed that the tissue extracts of PMM contained t-PA, and that those of AP contained both t-PA and urokinase-type plasminogen activator (u-PA). In addition, it appeared that u-PA in inflammatory tissue was related to proliferative changes of the mucous membrane.
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PMID:Presence of urokinase-type plasminogen activator (u-PA) in tissue extracts of antrochoanal polyp. 151 51

Nine healthy volunteers and 23 patients with various types of von Willebrand disease were studied before and after DDAVP infusion. We investigated the behaviour of factor VIII/von Willebrand factor measurements, and of tissue plasminogen activator and urokinase-type plasminogen activator. In mild von Willebrand disease the increase of both plasminogen activators was similar to that seen in normal controls. A different fibrinolytic behaviour was found in the type I platelet low and in the type III von Willebrand disease patients. An impaired and absent fibrinolytic response to DDAVP was seen in the former and in the latter von Willebrand disease, respectively. A close relation between either u-PA and t-PA or von Willebrand factor was observed. The possibility of a linkage among these three proteins was discussed.
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PMID:Urokinase-type plasminogen activator release after DDAVP in von Willebrand disease: different behaviour of plasminogen activators according to the synthesis of von Willebrand factor. 152 8

1. Extracts with physiological saline solution were obtained from about 20 species of invertebrates and seaweed. Tosyl-L-Arg-MeOH hydrolysing and fibrin plate lytic activity were detected in the invertebrates Stichopus japonicus, Crassost gigas, Tapes japonica, and Kintai-gai as well as the seaweed Codiales codium. 2. These activities were all labile against heat (at 65 degrees C for 1 hr). Except for the extract from Stichopus japonicus, lytic activities against fibrin plates with and without plasminogen were similar. 3. The extract from S. japonicus showed plasminogen activating potency as well as the existence of urokinase (UK) activity enhancing factor. 4. On the other hand, the extract of the seaweed Hizikia fusiformis showed a strong UK inhibiting activity. 5. A fraction of fibrinolytic enzyme was obtained from the extract of S. japonicus by absorption to the celite affinity chromatography. It was orally administered to rabbits at a dosage of 40 mg/kg/day. 6. Fibrinolytic activity was determined periodically on the eugloblin fraction of plasma samples collected from these animals. 7. As compared with the pretreatment value, the activity increased about 2 times (P less than 0.01) and 3 times (P less than 0.005) after 4 and 8 weeks, respectively, of the treatment. 8. After 8 weeks of treatment, the kidney of treated rabbits was extracted with 2 M KCl. The activity of tissue plasminogen activator (free-type TPA) was revealed to be enhanced significantly (P less than 0.001) in the extracts. 9. The fibrinolytic enzyme increased in the blood was recognized by zymography to be mainly the UK type plasminogen activator with mol. wt of 53,000.
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PMID:Fibrinolysis relating substances in marine creatures. 152 24


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