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)

Activated leukocytes release large amounts of chloramine like oxidizing agents (see Weiss et al. Science 222, 625-628, 1983) which inactivate protease inhibitors, creating microenvironments of uncontrolled protease activity. The biological result is an increased proteo- and fibrino- lysis. Functional determination of tissue type (t-PA) or urinary type (u-PA) plasminogen activator, the key enzymes of fibrinolysis, is of clinical importance. Assay techniques have been developed but are troublesome due to predilution, acidification or separation steps in order to eliminate the PA and plasmin inhibiting effect of plasmatic inhibitors of anti-PA and of anti-plasmin type, respectively. In this study, evidence is presented that performance of fibrinolytic assays using N-chloroamines offers great advantage: plasmatic plasminogen activator activity both of urinary and of tissue type can be measured precisely within minutes in untreated (direct) plasma samples. Therefore, mimicking the oxidative inflammatory response, for the first time it gets feasible to analyze blood factors involved in the physiological course of fibrinolysis by means of a functional, sensitive, and rapid assay procedure.
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PMID:A direct approach in fibrinolysis diagnostic: mimicry of the leukocyte by attack by oxidants. 251 6

The plasminogen activator activity (PAA) in extracts of the intima, media, and adventitia of the normal human aorta and other large arteries (carotid artery, renal artery and iliac artery) was studied with a sensitive, quantitative spectrophotometric assay using plasminogen and the chromogenic plasmin substrate S-2251. All layers of the arteries showed PAA which was highest in the adventitia, lowest in the media, while in the intima (aorta) PAA was intermediate, but much closer to that of the media. Plasminogen activator inhibition (PAI) was at the same level in all layers of the arteries studied. Plasmin inhibition (PI) was higher in adventitia than in intima (aorta), while in media the PI was intermediate. The PAA was due to the tissue-type plasminogen activator (t-PA), but not to the urokinase-type (u-PA), as judged by addition of respective antibodies. The relatively low PAA found in the intima of large arteries is therefore due to a low plasminogen activator and not a high plasminogen activator inhibitor activity or plasmin inhibitor level.
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PMID:Demonstration of plasminogen activator activity in the intima and media of the normal human aorta and other large arteries: immunological identification of the plasminogen activator(s). 252 44

Equimolar mixtures of recombinant single chain urokinase-type plasminogen activator (rscu-PA) and a murine monoclonal antibody (MA-15C5) directed against fragment-D dimer of human cross-linked fibrin were conjugated, using the cross-linking agent N-succinimidyl 3-(2-pyridyldithio)propionate (PySSProSu). The conjugate (rscu-PA/MA-15C5), purified by immunoadsorption on a urokinase antibody and affinity chromatography on fibrin fragment-D dimer with a yield of 42 +/- 15% (mean +/- SD, n = 3), contained an average of 1.2 +/- 0.3 IgG molecules/rscu-PA molecule. On non-reduced SDS/PAGE it migrated as a main band with apparent Mr of 200,000. Specific amidolytic activities expressed/mass of u-PA were less than 250 IU/mg for rscu-PA/MA-15C5 and rscu-PA, 140,000 +/- 13,000 IU/mg and 100,000 +/- 17,000 IU/mg for their plasmin-generated two chain derivatives rtcu-PA/MA-15C5 and rtcu-PA respectively. Specific activities on fibrin plates were 100,000 +/- 24,000 IU/mg and 130,000 +/- 49,000 IU/mg for rscu-PA/MA-15C5 and rtcu-PA/MA-15C5 respectively, as compared to 180,000 +/- 15,000 IU/mg for both rscu-PA and rtcu-PA. Activation of plasminogen with rscu-PA/MA-15C5 (Km = 0.37 +/- 0.16 microM, k2 = 0.0063 +/- 0.0030 s-1 or rtcu-PA/MA-15C5 (Km = 19 +/- 3.0 microM, k2 = 2.0 +/- 0.10 s-1) in purified systems followed Michaelis-Menten kinetics with Km and k2 values comparable to those of rscu-PA and rtcu-PA. In an in vitro system composed of a 125I-fibrin-labeled whole human plasma clot immersed in citrated human plasma, dose- and time-dependent lysis was obtained; 50% lysis in 2 h required 1.4 microgram/ml of rscu-PA or 0.33 microgram/ml of rtcu-PA, but only 0.22 microgram u-PA/ml of rscu-PA/MA-15C5 or 0.15 microgram u-PA/ml of rtcu-PA/MA-15C5. Addition of purified fragment-D dimer reversed the increased fibrinolytic potency of rscu-PA/MA-15C5 in a concentration-dependent way (50% inhibition at 7.2 micrograms fragment-D dimer/ml). Thus, conjugation of u-PA moieties with the fibrin-specific antibody MA-15C5 targets the plasminogen activator to the clot, resulting in a significant increase of their fibrinolytic potencies as compared to their unconjugated counterparts: 6.4-fold for rscu-PA and 2.2-fold for rtcu-PA.
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PMID:Biochemical properties of conjugates of urokinase-type plasminogen activator with a monoclonal antibody specific for cross-linked fibrin. 253 85

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

The secretion of elevated levels of proteinases is considered to be a distinct property of most transformed cells. The cellular and secreted levels of plasminogen activators and collagenases have been examined in the nonmalignant human osteosarcoma (HOS), the malignant Kirsten murine sarcoma virus transformed (KHOS/NP), the temperature sensitive revertant of virus transformed HOS (KHOS-240S) and N-methyl-N'-nitro-N-nitrosoguanidine transformed HOS (MNNG/HOS) clones. Virus and MNNG transformed clones exhibit 100- and 7-fold higher cellular and and 270- and 30-fold higher extracellular plasminogen activator (PA) activity as compared with untransformed HOS controls. The cellular PA activity of the revertant clone is similar to but the secreted level is slightly higher than the HOS controls. SDS-PAGE in the presence of casein and plasminogen is consistent with the major PA species of urinary type (u-PA) and with the absence of PA inhibitor in the parent and revertant clones. The cellular levels of active collagenase are low in all the clones. However, on activation by trypsin, the two active collagenase bands of similar intensity are observed for all the lines in SDS-PAGE in the presence of gelatin. While there appears to be some elevation of secreted collagenase prior to trypsin activation, the activated collagenases appear to have the same size and activity in all of the clones.
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PMID:Synthesis and secretion of plasminogen activators and collagenases in human cells transformed by Kirsten murine sarcoma virus and N-methyl-N'-nitro-N-nitrosoguanidine. 256 62

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

Human blood monocytes in culture differentiate to macrophagelike cells within 1 week. Coinciding with this morphological transition the cells started releasing increasing amounts of the serine proteinase plasminogen activator (PA; Mr 56,000) of the urokinase (u-PA) type and the proteinase inhibitor alpha-2-macroglobulin (alpha 2M). Unlike the cell-associated PA activity, which was also readily detected in fresh monocytes, the activity secreted into the serum-free culture medium could be measured only after treatment of the samples with sodium dodecyl sulphate. Heat or acid treatment of the medium was not sufficient to reveal the PA activity, suggesting that, apart from alpha 2M, another PA-inhibiting substance was present in the culture medium. The inhibitor (Mr 65,000) was found to be synthesized by macrophages and specifically inhibited u-PA activity but not tissue-type PA (t-PA) or plasmin activity. Dexamethasone decreased the secretion of PA by differentiated macrophages without affecting the production of alpha 2M or the PA inhibitor. Dexamethasone also inhibited the morphological differentiation of the cells when added to the monocyte-phase cells.
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PMID:Urokinase-type plasminogen activator and its inhibitor secreted by cultured human monocyte-macrophages. 257 31

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


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