Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Certain group A streptococci demonstrate surface receptors that bind selectively to the key fibrinolytic enzyme, plasmin. These bacteria show no reactivity with the zymogen protein plasminogen or with other serine class proteases, such as trypsin or urokinase. Bacterium-bound plasmin retains its ability to cleave synthetic substrates and its ability to hydrolyze a fibrin clot. The bacterium-bound plasmin is not effectively regulated by its physiological regulator, alpha 2-plasmin inhibitor. This study is the first report of a bacterium-associated receptor for plasmin.
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PMID:Identification of a specific receptor for plasmin on a group A streptococcus. 303 53

The thrombolytic effect of single-chain pro-urokinase (SCPU) was examined in the rabbit using a jugular vein thrombosis model. Infusion of a low dose (120,000 IU/kg) of either urokinase (UK) or SCPU did not produce any significant thrombolysis. However, UK administration at such a low dose caused 20% degradation of circulating fibrinogen. A high dose (480,000 IU/kg) caused significant thrombolysis. The degree of fibrinogenolysis was about 20% in SCPU, but about 80% in UK. The thrombolytic efficiency of SCPU was thus about 3 times larger than that of UK. Analysis of fibrinolytic parameters such as plasminogen, alpha 2-plasmin inhibitor, etc. suggested that UK caused systemic activation of the fibrinolytic system, but SCPU, locally limited activation on the fibrin surface (fibrinolysis). These results indicate that SCPU represents a highly efficient thrombolytic agent without producing fibrinogenolysis.
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PMID:Thrombolytic effect of single-chain pro-urokinase in a rabbit jugular vein thrombosis model. 308 8

We have previously demonstrated that plasminogen immobilized on various surfaces forms a substrate for efficient conversion to plasmin by tissue plasminogen activator (t-PA) (Silverstein, R. L., Nachman, R. L., Leung, L. L. K., and Harpel, R. C. (1985) J. Biol. Chem. 260, 10346-10352). We now report the binding of human plasminogen to the extracellular matrix synthesized in vitro by cultured endothelial cell monolayers. The binding was specific, saturable at plasma plasminogen concentrations, reversible, and lysine-binding site-dependent. Functional studies demonstrated that matrix immobilized plasminogen was a much better substrate for t-PA than was fluid phase plasminogen as shown by a 100-fold decrease in Km. Activation of plasminogen by t-PA and urokinase on the matrix was equally efficient. The plasmin generated on the matrix, in marked contrast to fluid phase, was protected from its fast-acting inhibitor, alpha 2-plasmin inhibitor. Matrix-associated plasmin converted bound Glu- into Lys-plasminogen, which in turn is more rapidly activated to plasmin by t-PA. The extracellular matrix not only binds and localizes plasminogen but also improves plasminogen activation kinetics and prolongs plasmin activity in the subendothelial microenvironment.
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PMID:Binding of plasminogen to extracellular matrix. 309 40

A new functional assay of PAI-activity in human plasma is described. Hitherto known assays for fast acting PAI have some disadvantages: predilution and/or acidification steps of the sample to afford the required inactivation of alpha-2-antiplasmin (A2-PI). This approach in contrast implicates test performance in presence of chloramine T (CT), an oxidant that destroys plasma antiplasmin activity without impairing significantly the activity of urokinase (u-PA) or plasmin. The following reaction conditions were found optimal: 50 microliter of undiluted plasma, anticoagulated with citrate or EDTA, were first incubated with 1 IU u-PA in a Tris-buffer, pH 8.4 and then with Glu-plasminogen (0.85 mumol/l final), CT (2.5 mmol/l final), tranexamic acid (0.9 mmol/l final) for 5 min. at 37 degrees C. After addition of 0.3 mmol/l of the chromogenic plasmin substrate H-D-Nva-CHA-Lys-pNA (pNA = para nitroanilide) and of NaCl (250 mmol/l final) a linear kinetic with delta A405/t in the range of 0.2/min for normal plasma was recorded. In an endpoint version of the test the chromogenic substrate can be added together with plasminogen resulting an A/t2-kinetic. Dilution studies showed a linear calibration curve from 0 to 14 arbitrary u-PA inhibiting units (AU)/ml plasma. By means of PAI-standard plasmas PAI-capacity values of 20 healthy volunteers (10 males/10 females) (x = 26 years, sigma = 4.2) were determined. They ranged from 0.4 - 6.9 (x = 1.3, sigma = 0.9) AU/ml plasma. Plasma samples containing more than 14 AU/ml were prediluted with PAI-deficient plasma. Intra- and inter-assay coefficients of variation (CV) were determined to be 1.3 +/- 0.6 and 4.3 +/- 0.5%, respectively. The values of this assay correlate well with those obtained by acidification of the samples. However, the possibility of measuring plasma PAI (and PA) activities by means of a simple and direct approach can be considered as an important progress with regard to routine hospital practice. The presented oxidative inactivation of A2-PI mimics the leukocyte attack phase, suggesting that activated leukocytes create a microenvironment of uncontrolled plasmin activity.
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PMID:Determination of plasminogen activator inhibitor (PAI) capacity of human plasma in presence of oxidants: a novel principle. 313 81

The effects of tissue-type plasminogen activator (t-PA) on the platelet aggregation were studied using citrated whole blood and platelet-rich plasma (PRP) obtained from human donors. t-PA suppressed adenosine 5'-diphosphate (ADP)- or collagen-induced platelet aggregation in a dose-dependent manner. The 50% inhibitory concentration (IC50) for t-PA was lower by one order of magnitude than that for urokinase (UK) in whole blood and PRP. The suppression of platelet aggregation was not completely inhibited by alpha-2-antiplasmin. t-PA did not cause the degradation of fibrinogen or fibrin in PRP, whereas UK caused the reduction of fibrinogen and fibrin, and the increase of fibrinogen- and fibrin-degradation products (FDP). These results suggest that the mode of action of t-PA in inhibiting platelet aggregation may be different from that of UK.
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PMID:Tissue-type plasminogen activator inhibits aggregation of platelets in vitro. 313 48

Lysine-plasminogen (Lys-PLG), the plasmin-modified form of native glutamic acid-plasminogen (Glu-PLG), displays enhanced binding affinity for fibrin and also enhanced activation by urokinase and tissue plasminogen activator. We previously demonstrated high-affinity, specific, and functional binding of Glu-PLG as well as tissue plasminogen activator to cultured human umbilical vein endothelial cells (HUVEC). In the present study, we demonstrate binding of Lys-PLG to HUVEC, as well as conversion of Glu-PLG to Lys-PLG at the cell surface. Binding of Lys-PLG to HUVEC was saturable, reversible, epsilon-aminocaproic acid-sensitive, and involved two saturable sites with Kd's of 142 pM and 120 nM, respectively. Upon incubation with Glu-PLG, HUVEC, as well as endothelium in situ, partially converted the ligand to a Lys-PLG-like species. Conversion by HUVEC was blocked by diisopropyl-fluorophosphate, but not by other serine protease inhibitors, including alpha 2-plasmin inhibitor. Eluates of intact umbilical cord vessels contained Lys-PLG by immunoblot analysis. Lys-PLG was also identified immunohistochemically on the endothelial surface of vessels from a variety of normal and inflamed tissues. Thus, endothelial cells appear to actively modify circulating Glu-PLG, bind Lys-PLG to their surface, and thus enhance the fibrinolytic potential of the blood vessel wall.
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PMID:Endothelial cell-mediated conversion of Glu-plasminogen to Lys-plasminogen. Further evidence for assembly of the fibrinolytic system on the endothelial cell surface. 314 82

The effect of tissue plasminogen activator (TPA) or urokinase on the specific binding of human Glu-plasminogen to fibrin I formed in plasma by clotting with Reptilase was studied using 125I-plasminogen and 131I-fibrinogen. In the absence of TPA, small amounts of plasminogen were bound to fibrin I. TPA induced binding of plasminogen to plasma fibrin I that was dependent upon the concentrations of TPA and plasminogen as well as upon the time of incubation. Plasminogen binding occurred in association with fibrin clot lysis and the formation in the clot supernatant of alpha 2-plasmin inhibitor-plasmin complexes. Urokinase also induced binding of plasminogen to plasma fibrin I that was concentration- and time-dependent. The molecular form of plasminogen bound to the fibrin I plasma clot was identified as Glu-plasminogen by dodecyl sulfate-polyacrylamide gel electrophoresis and by fast performance liquid chromatography. Further studies demonstrated that fibrin I formed from fibrinogen that had been progressively degraded by plasmin-bound Glu-plasminogen. The mole ratio of plasminogen bound increased with the time of plasmin digestion. Glu-plasminogen did not bind to fibrin I formed from fibrinogen progressively digested by human leukocyte elastase, thereby demonstrating the specificity of plasmin. These studies demonstrate that plasminogen activators regulate the binding of Glu-plasminogen to fibrin I by catalyzing plasmin-mediated modifications in the fibrin substrate.
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PMID:Tissue plasminogen activator and urokinase mediate the binding of Glu-plasminogen to plasma fibrin I. Evidence for new binding sites in plasmin-degraded fibrin I. 315 57

Correlation between the deposition of alpha 2-plasmin inhibitor (alpha 2-PI), which is one of the inhibitory factors of fibrinolytic activities, in the glomeruli and the effects of urokinase therapy in patients with IgA nephropathy is described. Urokinase (UK) is a plasminogen activator derived from fresh human urine. Urinalysis and measurements of renal function tests, i.e., serum creatinine, blood urea nitrogen, glomerular filtration rate and phenolsulfonphtalein, were performed before and at 8 and 48 weeks after the administration of urokinase. There was marked improvement of proteinuria after UK therapy in patients without deposition of alpha 2-PI in the glomeruli. In contrast, the improvement of proteinuria after UK therapy was not observed in patients with positive deposition of alpha 2-PI in the glomeruli. It was concluded that the administration of UK may be useful for treatment of proteinuria in patients with IgA nephropathy.
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PMID:Significant correlation between the immunofluorescence of alpha 2-plasmin inhibitor in glomeruli and the effects of urokinase therapy in patients with IgA nephropathy. 353 Jan 7

Intracoronary thrombolysis is a logical therapeutic method and one of the challenging new treatments of acute myocardial infarction. However, a wide dose range of urokinase has been reported, and the optimal dose has not yet been established. In this study the fibrinolytic activity in patients with recanalized coronary arteries was compared with that in those with nonrecanalized arteries. The mean doses of urokinase in the recanalized and non-recanalized groups were 910,700 +/- 161,730 international units (IU) and 1,008,000 +/- 151,800 IU, respectively. The fibrinolytic activity was measured with alpha 2-plasmin inhibitor, alpha 2-macroglobulin, fibrinogen, plasminogen, and fibrin degradation products. No significant difference was observed in the fibrinolytic activity between the recanalized and nonrecanalized groups. Because the fibrinolytic activity in the two groups was thought to be activated sufficiently and to a similar degree, it appears that 1,000,000 IU of urokinase is adequate for intracoronary thrombolysis and larger doses cannot be expected to result in a higher rate of recanalization.
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PMID:Dose of urokinase for intracoronary thrombolysis in patients with acute myocardial infarction. 362 94

Monoclonal antibodies to tissue type plasminogen activator (t-PA), urokinase (u-PA) and alpha-2-antiplasmin were obtained by immunizing Balb C mice with the respective purified antigens and fusion of spleen cells with mouse myeloma cells (NSO). The selected monoclonal antibodies reacted exclusively with the respective antigens used for immunization. 3 out of 7 monoclonal antibodies directed against t-PA inhibited plasminogen activation by t-PA and 6 of 7 interfered with the fibrin potentiating effect. Only one out of 5 monoclonal antibodies directed against u-PA inhibited plasminogen activation by u-PA. None of the monoclonal antibodies directed against t-PA or u-PA inhibited the cleavage of low molecular weight paranitroanilide substrates by the respective plasminogen activators. Likewise, the 3 monoclonal antibodies to alpha-2-antiplasmin did not functionally inhibit alpha-2-antiplasmin. The selected monoclonal antibodies were used to develop sensitive test systems for the respective antigens. The lower detection limit for determination of t-PA was found to be 0.5 ng/ml, for determination of u-PA 0.05 ng/ml, and for determination of alpha-2-antiplasmin 5 ng/ml.
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PMID:[Use of monoclonal antibodies in the diagnosis of fibrinolysis]. 403 6


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