Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of the interaction between heparin and plasmin not only on fibrinolytic, caseinolytic and esterolytic activities but also on amidolytic activity, since plasmin has amidolytic or amidase activity, was investigated. Following were the results obtained from these investigations: 1. Heparin enhanced amidolytic activity of a fixed level of plasmin which was prepared by activating plasminogen with urokinase within the range from 2 to 64 units/ml of the final concentration of heparin. 2. Heparin also enhanced amidolytic activity of a fixed level of plasmin which was prepared by converting plasminogen with insolubilized urokinase. 3. Heparin did not enhance or inhibit fibrinolytic, caseinolytic and esterolytic activities of a fixed level of plasmin which was prepared by activating plasminogen with urokinase, in the fibrinolytic activity within the range from 0.032 to 125 units/ml, in the caseinolytic activity within the range from 0.0125 to 100 units/ml, and in the esterolytic activity within the range from 0.016 to 128 units/ml, of the final concentration of heparin respectively.
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PMID:The interaction between heparin and plasmin on amidolysis. 16 69

Human antithrombin III was purified from fresh human plasma by affinity chromatography on heparin-Sepharose, affinity chromatography on concanavalin A Sepharose, gel filtration on Ultrogel AcA 34, ion exchange chromatography on DEAE A-50 Sephadex and preparative agarose gel electrophoresis. The hydrolytic activity of urokinase (plasminogen activator from urine) on acetyl-glycyl-L-lysine methylester acetate (Ac-gly-lys-OMeAc) was inhibited by antithrombin III in a slow time-dependent manner. Heparin accelerated the reaction between activator and inhibitor. Inhibition of catalytic activity was associated with the formation of an 1:1 molar complex between activator and inhibitor as revealed by sodium dodecyl sulphate polyacrylamide gel electrophoresis. The complex was also demonstrated by crossed immunoelectrophoresis against anti-antithrombin III.
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PMID:Inhibition of urokinase by complex formation with human antithrombin III in absence and presence of heparin. 70 90

Pulmonary thromboembolism is a widespread problem and is an important cause of death in patients with a variety of medical and surgical conditions. There have been few significant advances in the understanding of the aetiology beyond additional evidence confirming the importance of Virchow's triad. An impressive list of epidemiological associations has been compiled, however. Some knowledge of the natural progression of the disease is required as an aid in the understanding of the application of the therapeutic and prophylactic measures available in the management of pulmonary embolism. It would seem that at least two-thirds of pulmonary emboli are non-fatal, and in these cases the natural resolution, even of comparatively large embolic masses, is very efficient in patients without pre-existing cardiopulmonary disease. Diagnosis may prove difficult and most ancillary investigations are of questionable value. On the other hand, pulmonary radio-isotope scanning is far more specific and pulmonary angiography is a comparatively simple and complication-free diagnostic procedure. Prophylaxis is a real and practical aim, especially following surgery or myocardial infarction. In these groups widespread clinical trials of prophylactic measures have been made possible by the objective radio-iosotope screening techniques. Mechanical means of preventing venous stasis and anticoagulation appear effective. In addition, low-dose subcutaneous heparin seems to be as useful as heparin in conventional dosage. Apart from conventional supportive therapy, there are three major approaches to the treatment of pulmonary embolism. Heparin remains the mainstay, particularly in the less severe cases, hopefully preventing propogation of thrombosis and recurrence of embolism, thus allowing resolution to take place. Thrombolytic therapy with streptokinase or urokinase is capable of producing far more rapid dissolution of pulmonary emboli with consequent theoretical advantages over heparin. No reduction in mortality has been shown using thrombolytic therapy. Patients who fail to respond satisfactorily to acute resuscitative measures may require pulmonary embolectomy.
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PMID:Pulmonary embolism: current therapeutic concepts. 77 78

Experimental studies on rabbit ears amputated by either a clean sharp division or severed by a crushing blow showed that twice as much blood remained in the crush group. Microthrombi and tissue thrombi were seen in this group only. A review of 142 digital replantations performed over a 10 year period showed 126 survivals. Ninety-three were complete amputations and 80 of these survived; 49 were incomplete amputations and 46 survived after revascularization attemps. Of 74 clear amputations, 68 survived; of 68 crush-type amputations, 58 survived. Circulatory disturbances occurred in 36 replanted digits; 16 could not be salvaged. The primary cause of complications was venous obstruction. In 80 digital replantations done from January, 1974, to December, 1975, success was obtained in 75 (93.75 percent). Irrigation of vessels of the severed part is done only in cases of double level amputation, severely crushed or those due to avulsion. Heparin, low molecular weight dextran, urokinase, and antibiotics are given for several days after operation.
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PMID:Traumatic amputation of digits: the fate of remaining blood. An experimental and clinical study. 83 50

How heparin inhibits vascular smooth muscle cell proliferation and migration has not been established. We have investigated the hypothesis that heparin inhibits vascular smooth muscle cell proliferation and migration by interfering with the expression and activity of proteases such as plasminogen activators. In an in vitro mitogenesis model, tissue-type plasminogen activator (tPA) mRNA and protein increase in baboon smooth muscle cells stimulated with fetal bovine serum or phorbol esters. Heparin inhibits smooth muscle cell proliferation and suppresses the induction of tPA mRNA and protein while it has little effect on the mRNA of urokinase-type plasminogen activator, plasminogen activator inhibitor type I, and a number of genes that are also modulated by serum and phorbol esters. The inhibitory effect on tPA mRNA is specific to heparin-like molecules and does not depend on the anticoagulation activity of heparin. The increase in tPA mRNA is due to increased transcription, which is suppressed by heparin. The induction of tPA by serum and phorbol esters is diminished by protein kinase C inhibitors such as H7 or staurosporine and by protein kinase C depletion. Since heparin suppresses the induction of the tPA gene by phorbol esters, these results suggest that heparin may interfere with the protein kinase C pathway.
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PMID:Heparin selectively inhibits the transcription of tissue-type plasminogen activator in primate arterial smooth muscle cells during mitogenesis. 131 Jun 87

Protein C inhibitor is a plasma protein whose ability to inhibit activated protein C, thrombin, and other enzymes is stimulated by heparin. These studies were undertaken to further understand how heparin binds to protein C inhibitor and how it accelerates proteinase inhibition. The region of protein C inhibitor from residues 264-283 was identified as the heparin-binding site. This differs from the putative heparin-binding site in the related proteins antithrombin and heparin cofactor. The glycosaminoglycan specificity of protein C inhibitor was relatively broad, including heparin and heparan sulfate, but not dermatan sulfate. Non-sulfated and non-carboxylated polyanions also enhanced proteinase inhibition by protein C inhibitor. Heparin accelerated inhibition of alpha-thrombin, gamma T-thrombin, activated protein C, factor Xa, urokinase, and chymotrypsin, but not plasma kallikrein. The ability of glycosaminoglycans to accelerate proteinase inhibition appeared to depend on the formation of a ternary complex of inhibitor, proteinase, and glycosaminoglycan. The optimum heparin concentration for maximal rate stimulation varied from 10 to 100 micrograms/ml and was related to the apparent affinity of the proteinase for heparin. There was no obvious relationship between heparin affinity and maximum inhibition rate or degree of rate enhancement. The affinity of the resultant protein C inhibitor-proteinase complex was also not related to inhibition rate enhancement, and the results showed that decreased heparin affinity of the complex is not an important part of the catalytic mechanism of heparin. The importance of protein C inhibitor as a regulator of the protein C system may depend on the relatively large increase in heparin-enhanced inhibition rate for activated protein C compared to other proteinases.
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PMID:Heparin binding to protein C inhibitor. 131 38

Neutrophils (polymorphonuclear neutrophils [PMNs]) have been implicated as mediators of reperfusion injury. Heparin, urokinase, and ancrod are agents used routinely to prevent and treat thrombosis, yet their effects on PMN function are unknown. Therefore human PMNs were obtained and incubated for 30 minutes with either saline solution or one of the following pharmacologic agents, each tested at three different concentrations: group 1, saline solution (control, n = 14); groups 2 through 4, heparin (5000 units/ml, n = 8; 2500 units/ml, n = 6; and 1250 units/ml, n = 6, respectively); groups 5 through 7, urokinase (50,000 units/ml, n = 8; 25,000 units/ml, n = 6; and 12,500 units/ml, n = 6, respectively), and groups 8 through 10, ancrod (70 units/ml, n = 8; 35 units/ml, n = 6; and 17.5 units/ml, n = 6). Superoxide anion production was measured by the reduction of cytochrome c in a spectrophotometric assay. Chemotaxis was evaluated by the number of PMNs migrating across a filter with a Neuro Probe chamber (Neuro Probe, Cabin John, Md.). Phagocytosis was determined by the ingestion of opsonized zymosan particles by PMNs. Serum obtained from each PMN donor was used both to opsonize the zymosan and as a chemoattractant in the chemotaxis assay. Statistical comparison was evaluated by analysis of variance, and post hoc comparisons for each agent with control were performed with the unpaired Student t test. No agent, at any dose, significantly changed superoxide anion production compared with control cells. All three agents significantly inhibited PMN chemotaxis (p < 0.01). In the control group the number of PMNs counted was 27.6 +/- 4.9.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Heparin, urokinase, and ancrod alter neutrophil function. 132 94

The chimeric molecule K1K2Pu, comprising the two kringle domains (K1 and K2) of tissue-type plasminogen activator (t-PA) and the COOH-terminal region with the serine protease domain (Pu) of urokinase-type plasminogen activator (u-PA), was previously shown to have a 5- to 10-fold reduced clearance rate with maintained specific thrombolytic activity, resulting in an increased thrombolytic potency in animal models of venous and arterial thrombosis. To document the thrombolytic potential of K1K2Pu, the thrombolytic potency and fibrin specificity were studied in a combined platelet-rich arterial eversion graft thrombosis and venous whole blood clot model in heparinized dogs (100 U/kg bolus and 50 U/kg per h infusion). Dose-response effects of bolus injections of K1K2Pu (0.032 to 0.25 mg/kg) were compared with those of recombinant t-PA (rt-PA) and of recombinant single chain u-PA (rscu-PA) (0.25 to 1.0 mg/kg each) in groups of five or six dogs, each given heparin with or without the thromboxane synthase inhibitor/prostaglandin endoperoxide receptor antagonist ridogrel. Heparin and ridogrel in the absence of a thrombolytic agent did not produce arterial reflow or venous clot lysis in five dogs. Addition of K1K2Pu, rt-PA or rscu-PA resulted in a dose-dependent induction of arterial reflow and of venous clot lysis in the absence of systemic fibrinolytic activation and fibrinogen breakdown. Consistent arterial reflow required 0.063 mg/kg of K1K2Pu and 0.5 mg/kg of rt-PA or of rscu-PA. The thrombolytic potency for venous clot lysis, expressed as percent lysis per mg compound administered per kg body weight, was (mean +/- SEM) 750 +/- 160 for K1K2Pu, 68 +/- 17 for rscu-PA (p less than 0.001 vs. K1K2Pu) and 110 +/- 29 for rt-PA (p less than 0.001 vs. K1K2Pu). The plasma clearance rates were significantly lower for K1K2Pu than for rscu-PA and rt-PA. In the absence of ridogrel, arterial reflow was significantly slower and was followed by cyclic reocclusion and reflow; however, venous clot lysis was unaffected. Template bleeding times were not significantly altered in the absence but were markedly prolonged in the presence of ridogrel. These results confirm and establish that, when given as a bolus injection, K1K2Pu has an approximately 10-fold higher thrombolytic potency for arterial and venous thrombolysis than does rt-PA or rscu-PA. Thrombolysis with K1K2Pu is obtained in the absence of systemic fibrinolytic activation and fibrinogen breakdown. These properties suggest that K1K2Pu offers potential for thrombolytic therapy by bolus administration in patients with thromboembolic disease.
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PMID:Comparative thrombolytic properties of tissue-type plasminogen activator (t-PA), single-chain urokinase-type plasminogen activator (u-PA) and K1K2Pu (a t-PA/u-PA chimera) in a combined arterial and venous thrombosis model in the dog. 134 79

Smooth muscle cells (SMCs) in balloon-injured rat carotid artery express tissue-type plasminogen activator (t-PA) at a time when they are migrating from the media to the intima. Since heparin inhibits SMC migration and intimal thickening, we have examined the possibility that heparin might also inhibit t-PA expression. Heparin (nonanticoagulant fraction; molecular weight, approximately 6,000) was administered by continuous intravenous infusion (1.0 mg/kg per hour) to Sprague-Dawley rats subjected to balloon injury of the left common carotid artery. At various times up to 14 days after injury, plasminogen activator expression was analyzed by zymography, plasmin generation, enzyme-linked immunosorbent assay, Northern blotting, and in situ hybridization. This dose of heparin inhibited SMC accumulation at 14 days by 60%. Both urokinase plasminogen activator (u-PA) and t-PA activity increased in injured arteries and reached a maximum at 7 days. Heparin treatment decreased t-PA, but not u-PA, activity. Total t-PA protein was decreased by treatment with heparin but not chondroitin sulfate, and the decrease in t-PA protein was associated with decreased t-PA mRNA in the media. These results in the injured rat carotid artery agree with our earlier observations that heparin inhibits t-PA gene expression in cultured baboon aortic SMCs. They also provide support for the hypothesis that heparin interferes with the expression of certain proteases required for SMC migration and proliferation.
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PMID:Heparin inhibits the expression of tissue-type plasminogen activator by smooth muscle cells in injured rat carotid artery. 137 98

The binding of urokinase to immobilized heparin and dextran sulfate was studied using activity assays of the bound urokinase. The markedly higher binding observed with high M(r) urokinase compared to low M(r) urokinase indicated a role for the amino-terminal fragment (ATF). This was confirmed by the use of inactive truncated urokinase and monoclonal antibodies specific for the ATF in competition assays of urokinase binding. Antibody competition assays suggested a site in the kringle domain, and a synthetic decapeptide Arg-52-Trp-62 from the kringle sequence (kringle numbering convention) was competitive in assays of urokinase binding to dextran sulfate and heparin. Heparin binding to the urokinase kringle was unambiguously demonstrated via 1H NMR spectroscopy at 500 MHz. Effective equilibrium association constants (K(a)*) were determined for the interaction of isolated kringle fragment and low M(r) heparin at pH 7.2. The binding was strong in salt-free 2H2O (K(a)* approximately 57 mM-1) and remained significant in 0.15 M NaCl (K(a)* approximately 12 mM-1), supporting a potential physiological role for the interaction. This is the first demonstration of a function for the kringle domain of urokinase, and it suggests that while the classical kringle structure has specificity for lysine binding, there may also exist a class of kringles with affinity for polyanion binding.
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PMID:Heparin binding to the urokinase kringle domain. 151 Sep 44


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