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)

We have studied the mechanism of release of plasminogen activator (PA) activity induced by epinephrine in the perfused rat hindleg model. Epinephrine perfusion at the dose of 12.5 microM caused a slighter effect on PA activity but an immediate increase in the perfusion pressure. At 25 microM, epinephrine induced a marked increase in PA activity that reached the maximum level at the end of the drug perfusion. The same response was induced by repeated stimulations with epinephrine (25 microM) only if the second stimulus was given 20-25 min apart from the first one. PA release could be blocked by propranolol (300 microM), a nonspecific beta-blocker, and not by phentolamine, a nonspecific alpha-blocker, unless used at very high concentrations (1,250 microM). Perfusion with dibutyryl adenosine 3',5'-cyclic monophosphate (DbcAMP) alone induces an immediate and transient increase in PA activity, but no potentiation could be demonstrated if theophylline was perfused together with epinephrine. The released PA has been characterized on the basis of molecular weight and immunological criteria as t-PA- and u-PA-like molecules in basal conditions. Epinephrine perfusion induced an increase only in the t-PA-like protein. These data indicate that the release of t-PA-like activity observed after epinephrine perfusion is mainly mediated by beta-receptors and is independent from its vasoactive action.
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PMID:Tissue-type plasminogen activator release in response to epinephrine in perfused rat hindlegs. 253 33

Increased blood loss (BL) has been reported after cervical dilatation by laminaria tent in legal abortions. The BL was measured in 72 women in whom first trimester legal vacuum aspiration was performed. The cervical canal was dilatated by laminaria tent in 37 patients, and mechanically with Hegar dilators in 35 patients. BL was studied in relation to the plasminogen activators (u-PA, t-PA) and the plasminogen activator inhibitors (PAI-1, PAI-2) in the decidua and placenta. There was no significant difference in BL between the two groups. Decidual PAI-1 concentrations were significantly higher in the laminaria tent group than in the Hegar dilator group. An inactivation of u-PA by PAI-1 might explain the lack of increase in BL among the laminaria tent group.
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PMID:The effect of cervical dilatation by laminaria tent in first trimester legal abortions on blood loss related to fibrinolytic activity in the decidua and placenta. 256 33

Seven mouse monoclonal antibodies have been produced against human melanoma tissue plasminogen activator (t-PA). They were specifically bound to 125I t-PA but not 125I urokinase (u-PA) and inhibited t-PA, but not u-PA, activity in plasminogen-rich 125I fibrin wells. Three of the antibodies directly inhibited the amidolytic activity of t-PA and the two most effective also bound near the active site histidine residue as determined by competition experiments using active site blocking agents. Several antibodies interfered with the fibrin binding properties of t-PA. One antibody neither interacted with the active site nor inhibited fibrin binding but still effectively quenched t-PA activity in fibrin wells suggesting that it masks another region of the molecule necessary for effective biological activity.
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PMID:Characterisation of epitopes on human tissue plasminogen activator recognised by a group of monoclonal antibodies. 258 30

Plasminogen activators initiate the fibrinolytic system by conversion of the proenzyme plasminogen to the active fibrin degrading enzyme plasmin. Plasminogen activator inhibitors inhibit the effects of both plasminogen activators. Uncomplicated pregnancies are accompanied by hypercoagulability and an increased risk of thromboembolic disease. Thrombosis is rare in the first trimester and most events are noted in the last trimester. Therefore, we studied the fibrinolytic system at the end of pregnancy and in the puerperium. Plasma concentrations of urokinase plasminogen activator (u-PA/competitive radioimmunoassay), tissue type plasminogen activator (t-PA/sandwich ELISA) and plasminogen activator inhibitor (PAI/functional assay) were determined in 44 women (age: 24.3 +/- 4.3 years) with normal pregnancy near term. Plasma samples were collected before the onset of labour and 1, 2, 3, 4 and 5 days after delivery. Compared with an age-matched non pregnant control group (8.3 +/- 3.94 U/ml) significantly increased PAI activity (12.13 +/- 4.79 U/ml - p less than 0.005) was measured before delivery with a subsequent significant decrease (8.13 +/- 1.97 U/ml) to normal values on day 1 after delivery; plasma u-PA and t-PA antigen levels remained unchanged. Placental weight and birth weight had no influence on plasma levels of both plasminogen activators.
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PMID:Influence of delivery on plasminogen activator inhibitor activity. 268 64

The effect of a selective thrombin inhibitor, (2R, 4R)-4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]- L-arginyl]-2-piperidinecarboxylic acid (MCI-9038), on the fibrinolysis induced by t-PA and u-PA was studied in vitro and in vivo. MCI-9038 remarkably reduced the lysis time of the plasma clot generated by the addition of calcium chloride to the plasma at the concentration ranging from 0.01 to 0.3 microM. Heparin also reduced the plasma clot lysis time with a lower effect than MCI-9038. The fibrin crosslinkage in the plasma clot was inhibited by MCI-9038 or heparin. MCI-9038 potently inhibited the factor XIIIa generation from factor XIII by thrombin. The effect on the in vivo thrombolysis was studied on the arterial thrombosis generated by the endothelial cell injury of the rabbit carotid artery by acetic acid. t-PA dissolved the thrombi with the infusion at 0.96 mg/kg over 2 h without a significant activation of a systemic fibrinolysis. u-PA dissolved the thrombi with the infusion at 180,000 and 360,000 IU/kg over 2 h. At a dose of 0.48 mg/kg t-PA or 90,000 IU/kg u-PA, the thrombi were not dissolved, but the combined use of MCI-9038 at 1.2 mg/kg over 2 h effectively dissolved the thrombi. Thus, combination of MCI-9038 with plasminogen activators accelerated thrombolysis of an experimental thrombosis in rabbits.
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PMID:Effect of a selective thrombin inhibitor MCI-9038 on fibrinolysis in vitro and in vivo. 287 8

The kinetic parameters of three activator species of Glu1-plasminogen (Glu1-Plg) were compared in their reaction at pH 7.4 and 37 degrees C, in the presence and absence of CNBr-digested fibrinogen (CNBr-Fg). The urokinase- (u-PA-) derived covalent hybrid activator PlnA-u-PAB had an apparent Michaelis constant (Kplg) of 7.44 microM, a catalytic rate constant (kplg) of 51.1 min-1, and a second-order rate constant (kplg/Kplg) of 6.87 microM-1 min-1. The tissue plasminogen activator (t-PA) derived covalent hybrid activator PlnA-t-PAB was characterized by a Kplg of 3.33 microM, a kplg of 1.03 min-1, and a kplg/Kplg of 0.309 microM-1 min-1. The kplg/Kplg values for the parent u-PA and t-PA activators were 6- and 16-fold higher than the respective hybrids, mainly due to an approximately 10-fold increase in the apparent Kplg for the hybrids. In the presence of CNBr-Fg, the increase of the kplg/Kplg values for u-PA and its hybrid was 1.1-fold, but for t-PA and its hybrid, the increases were 7- and 12-fold, respectively. In both the absence and presence of CNBr-Fg, activator t-PAB had an apparent Kplg of 19.1 and 27.6 microM and a kplg of 2.9 and 5.0 min-1, respectively. The increase in the kplg/Kplg value with CNBr-Fg was 1.2-fold. The streptokinase- (SK-) derived activators Glu1-plasmin.SK (Glu1-Pln.SK), Val442-Pln.SK, and Val561-Pln.SK had apparent Kplg values of 0.458, 0.268, and 0.121 microM and kplg values of 20.0, 126.0, and 63.3 min-1, respectively. In the presence of CNBr-Fg, the first two activators showed an approximately 1.4-fold increase and the last showed a 1.4-fold decrease in their kplg/Kplg values. The catalytic efficiency (kplg/Kplg) of the various activator species fell in the decreasing order SK greater than u-PA greater than t-PA, in either the presence or absence of CNBr-Fg. CNBr-Fg enhanced significantly the activities of only two activators, t-PA and PlnA-t-PAB.
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PMID:Kinetic analysis of covalent hybrid plasminogen activators: effect of CNBr-degraded fibrinogen on kinetic parameters of Glu1-plasminogen activation. 297 23

Two types of plasminogen activator (PA), t-PA (tissue type) and u-PA (urokinase type), are released from endometrial tissue in organ culture, as judged by immunological identification and molecular weight. Addition of estradiol to the medium greatly enhanced the release of u-PA, whereas that of t-PA was not low. Addition of progesterone, on the other hand, after priming of the endometrial tissue with estradiol, resulted in a much lower release of both types of PA. This pattern of PA release in response to hormonal stimulation in vitro agrees with previous observations of the PA activity of endometrial secretion in vivo. Endometrial tissue also released a PA inhibitor with molecular weight of approximately 50,000, which complexed both t-PA and u-PA. In cultures stimulated with estradiol the amount of free u-PA increased gradually during incubation and minor amounts of free t-PA appeared after 4-6 days culture. The amount of complexes, and thus the amount of PA inhibitor also increased under influence of estradiol. In cultures stimulated with progesterone, on the other hand, only minor amounts of free u-PA and no free t-PA was detected. The inhibitor might be of either the endothelial or the placental type, or both.
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PMID:Hormonal regulation of the release of plasminogen activators and of a specific activator inhibitor from endometrial tissue in culture. 309 May 54

Plasminogen activators (PA) convert the inactive proenzyme plasminogen into plasmin, which is involved in the process of fibrinolysis, tissue remodeling, and cell migration. There are two distinct forms of PA: urokinase (u-PA) and tissue-type plasminogen activator (t-PA). t-PA has higher affinity for fibrin and is the main form involved in thrombolysis. By in situ chromosomal hybridization and Southern blot analysis of somatic cell hybrid DNA, we have assigned the human t-PA gene to chromosome 8, bands 8p12----q11.2. We have detected a common EcoRI restriction fragment length polymorphism within the t-PA gene that thus provides a precisely localized highly informative marker for genetic linkage studies. The t-PA gene localization coincides with a translocation breakpoint observed in myeloproliferative disorders. Whereas leukemic cells usually secrete both types of PA, a correlation exists between acute myeloid leukemic cells that release only t-PA and failure to respond to chemotherapy.
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PMID:Human tissue-type plasminogen activator gene located near chromosomal breakpoint in myeloproliferative disorder. 309 43

Plasminogen activators (PAs) present in the plasma of BALB/c mice and produced in vitro by murine tumor cell cultures (B77-3T3, SR-BALB, AA6) have been characterized using electrophoretic-zymographic techniques. BALB/c mouse plasma contains a main PA activity with an approximate molecular weight of 88,000 and pI 6.3, inhibited by anti-human tissue-type plasminogen activator (t-PA) serum, here defined as murine t-PA. On the contrary, all tumor cells tested release a PA activity with a molecular weight of 44,500 and pI 9.2 characteristic of urokinase-type activator (murine u-PA). The injection s.c. of the different tumorigenic cells into BALB/c mice leads to tumor development and to a rapid increase of t-PA from the first day following the injection. This early enhancement of t-PA activity is not detectable in mice given injections of lethally irradiated B77-3T3 cells. Moreover the development of the tumor in the animals is related to the appearance of increasing levels of u-PA in the blood. This activity is detectable in the plasma of treated mice almost 2 wk before detection of a tumor 1 mm in diameter. During tumor development, the molecular weight of the u-PA and t-PA forms present in the plasma does not change, while there is a decrease of the isoelectric point of the u-PA leading to the appearance of distinct PA activities with pI 7.6 and 8.9. Syngenic and allogenic lymphocytes, injected in BALB/c mice, do not induce any modification in the pattern of the plasma PA. The injection of highly metastatic cells, as opposed to nonmetastatic or low-metastatic cells, does not give rise to detectable levels of u-PA in the plasma of treated mice. These data suggest that the lack of plasma u-PA activity facilitates the formation of metastates, while the increase of this activity is important in tumor development and is independent of the metastatic potential of the injected cells.
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PMID:Relationship between circulating plasminogen activators and tumor development in mice. 309 69

alpha-Thrombin, DFP-thrombin, and ionophore A23187 induce the rapid release (less than 5 minutes) of a variety of proteins, including t-PA forms (Mr 110 and 70 k, after SDS-PAGE) from primary cultures, and both t-PA and u-PA (Mr 90 and 54 k) from subcultured human HUVECs. All PA activity forms are rapidly decreased in the releasates by some unknown mechanism. gamma-Thrombin does not induce the release of PAs from cultured HUVECs.
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PMID:Rapid release and deactivation of plasminogen activators in human endothelial cell cultures in the presence of thrombin and ionophore A23187. 309 27


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