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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 specific cellular receptor for urokinase-type plasminogen activator (uPA) is found on a variety of cell types and has been postulated to play a central role in the mediation of pericellular proteolytic activity. We have studied the kinetics of plasminogen (Plg) activation catalyzed by uPA specifically bound to its receptor on the human monocytoid cell-line U937 and demonstrate this process to have properties differing widely from those observed for uPA in solution. The solution-phase reaction was characterized by a Km of 25 microM and for the cell-associated reaction this fell 40-fold to 0.67 microM, below the physiological Plg concentration of 2 microM. A concomitant 6-fold reduction in kcat resulted in an increase in the overall catalytic efficiency, kcat/Km, of 5.7-fold. This high affinity Plg activation was abolished in the presence of a Plg-binding antagonist. In contrast to intact cells, purified uPA receptor (isolated from phorbol 12-myristate 13-acetate-stimulated U937 cells) was observed to partially inhibit uPA-catalyzed Plg activation, although activity against low molecular weight substrates was retained. Therefore, the cellular binding of Plg appears to be of critical importance for the efficient activation of Plg by receptor-bound uPA. Plasmin generated in the cell-surface Plg activation system described here was also observed to be protected from its principal physiological inhibitor alpha-2-antiplasmin. Together, these data demonstrate that the cell surface constitutes the preferential site for Plg activation when uPA is bound to its specific cellular receptor, which therefore has the necessary characteristics to play an efficient role in the generation of pericellular proteolytic activity.
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PMID:Plasminogen activation by receptor-bound urokinase. A kinetic study with both cell-associated and isolated receptor. 182 61

We present evidence that over-expression of human plasminogen, the precursor to the serine protease plasmin, can be cytotoxic to mammalian cells. When an expression vector containing plasminogen cDNA is transfected into baby hamster kidney cells, the number of drug-resistant colonies as well as the levels of plasminogen secreted by those colonies is lower than observed in similar transfections of other protease precursor genes. The recombinant plasminogen accumulates intracellularly as degraded NH2-terminal fragments. In contrast, a mutant of plasminogen that produces inactive plasmin (active site Ser740 changed to Ala) is synthesized by these cells as a full-length plasminogen molecule, and the colony numbers and expression levels are normal. Thus, the generation of plasmin activity is responsible for the cytotoxic phenomena and the degradation associated with plasminogen expression. In addition, experiments using a plasminogen mutant that cannot be activated to plasmin (activation cleavage site Arg560 to Gly) or using coexpression of antisense urokinase RNA indicate that an endogenous plasminogen activator is responsible for converting newly synthesized plasminogen to plasmin. Finally, coexpression of plasminogen with alpha 2-plasmin inhibitor, a serpin which is the physiologic inhibitor of plasmin, prevents the toxic effects of intracellular plasmin activity and allows the synthesis and secretion of native human plasminogen.
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PMID:Expression of recombinant human plasminogen in mammalian cells is augmented by suppression of plasmin activity. 183 Dec 1

Intravenous administrations of 2000 x 10(4)IU (33 mg) (rt-PA2) and 3000 x 10(4)IU (50 mg) (rt-PA3) of a new recombinant tissue plasminogen activator (rt-PA:TD-2061) derived from uterine endothelial cells and urokinase (UK) 96 x 10(4)IU were compared in a double blind, randomized trial of 198 patients with evolving myocardial infarction. All patients entered the trial within 6 h of the onset of symptoms and underwent baseline coronary angiography of the infarct-related coronary artery before thrombolytic therapy was instituted. Sixty minutes following thrombolytic therapy occluded infarct-related arteries were successfully reperfused in 41.5% of 66 patients in the UK, 76.4% of 72 patients in the rt-PA2, and 74.6% of 59 patients in the rt-PA3 group. Statistically significant differences were observed between the UK and rt-PA groups (p less than 0.01). Serum fibrinogen levels declined in all 3 groups at 60 min post-therapy by averages of 35.9 +/- 3.1% in the UK, 16.8 +/- 4.8% in the rt-PA2 and 17.5 +/- 4.5% in the rt-PA3 group. The difference between the UK and the rt-PA groups was statistically significant (p less than 0.01). Plasma plasminogen and alpha 2-plasmin inhibitor levels showed the same tendencies. Bleeding was the most commonly observed complication and was most commonly seen at the catheterization site. There was no difference in the incidence among the 3 groups. Hospital deaths occurred in 5.3%, 6.3%, and 4.7% of the cases in the UK, rt-PA2 and rt-PA3 groups, respectively. We conclude, therefore, that rt-PA achieves a significantly higher rate of recanalization with less extensive systemic fibrinogenolysis at the dose employed than does UK. The optimum intravenous dose of rt-PA for Japanese patients is considered to be 2000 x 10(4)IU (33 mg).
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PMID:Intravenous recombinant tissue-type plasminogen activator (rt-PA) and urokinase (UK) in patients with evolving myocardial infarction--a multicenter double-blind, randomized trial in Japan. 190 67

Tissue-type plasminogen activator (t-PA) is thought to be a promising fibrinolytic agent because of its high affinity to fibrin without evidence of significant systemic fibrinolysis. The feasibility of t-PA and urokinase (UK) in local fibrinolytic therapy was investigated in a canine common carotid artery thrombus model. After the screening of coagulation-fibrinolytic activities, autologous blood clot was injected into the segment of intimal injured common carotid artery. The fibrinolytic agent was locally applied from the origin of the common carotid artery under temporary flow arrest with a double lumen balloon catheter. T-PA used in this study was produced by the cell culture technique of normal human cells. Its activity was-expressed by AK units (AKU), namely, the fibrinolytic area of the fibrin-agar plate induced by 10 AKU/ml of t-PA solution corresponds to that of 10 IU/ml of UK solution. The doses of t-PA required to produce angiographical recanalization were 600-1,200 AKU/kg (approximately 0.015-0.03 mg/kg) of t-PA, while 24,000 IU/kg was necessary for UK. In these doses, t-PA evoked no adverse effects on the plasma coagulation-fibrinolytic system, while UK produced significant decrease in plasma fibrinogen and alpha-2 plasmin inhibitor levels. Thus, t-PA may be considered to have higher fibrinolytic ability and lower adverse effect on the plasma coagulation-fibrinolytic system than UK. Local fibrinolytic therapy for acute cerebral infarction using t-PA is considered to be a promising intravascular therapeutic procedure with less systemic fibrinolytic complications such as hemorrhagic infarction.
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PMID:[An experimental study of local fibrinolysis using tissue plasminogen activator and urokinase in a canine common carotid artery thrombus model]. 211 1

Recombinant single-chain urokinase-type plasminogen activator was intravenously administered in 2 different doses in 24 patients with acute myocardial infarction and angiographically proved occlusion of the infarct-related artery. Patients with first infarction without contraindications of thrombolysis were treated within the first 4 hours after the onset of symptoms. Group A (12 patients) received 20 mg of rscu-PA as a bolus followed by 60 mg infused over 1 hour and group B received 10 mg as a bolus and 30 mg as infusion. The 2 groups showed no significant difference in age, sex, height, weight, time between onset of symptoms and start of therapy, peak values and course of infarct-related enzymes. Time to reperfusion was 43 minutes in group A versus 67 minutes in group B (p less than 0.005). The rate of reperfusion 90 minutes after start of treatment was 91% in group A and 50% in group B (p less than 0.001). Plasma levels of fibrinogen, plasminogen and alpha-2-antiplasmin did not differ significantly in both groups. Systemic lytic state (fibrinogen less than 100 mg/dl) occurred in 33% of group A and in 9% of group B. Intravenous infusion of 80 mg (but not 40 mg) of rscu-PA led to reperfusion of the occluded coronary artery in nearly all patients. Approximately one-third of the patients treated with this dose demonstrated systemic lysis.
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PMID:Recombinant single-chain urokinase-type plasminogen activator during acute myocardial infarction. 245 63

Hyperfibrinolytic states are reported to be a cause of bleeding in patients with amyloidosis. We reviewed the literature on excessive fibrinolysis in association with amyloidosis and report our findings from a patient with idiopathic amyloidosis who developed a bleeding diathesis. Coagulation laboratory studies indicated elevated plasminogen activator levels associated with a reduction of plasminogen and alpha 2-plasmin inhibitor (alpha 2-PI) levels. The level of tissue-type plasminogen activator (t-PA) inhibitor and t-PA antigen were normal. However, the patient did have a five- to sevenfold increase in amidolytic activity for the urokinase substrate pyro-Glu-Gly-Arg-pNA (S-2444). This case therefore represents a novel example of a hyperfibrinolytic state associated with amyloidosis caused by elevated urokinase-type plasminogen activator (u-PA). Epsilon-amino caproic acid (EACA) therapy resulted in an increase in alpha 2-PI and plasminogen levels and effectively reduced the blood loss. Hyperfibrinolytic states in amyloidosis have now been reported to be due to elevated t-PA and u-PA and depleted t-PA inhibitor.
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PMID:Elevated urokinase-type plasminogen activator level and bleeding in amyloidosis: case report and literature review. 249 17

We studied the effects of FR-860 on coagulative and fibrinolytic activities in human plasma compared to conventional unfractionated heparin (UF-heparin). Both FR-860 and UF-heparin dose-dependently prolonged the recalcification time, activated partial thromboplastin time, prothrombin time, factor Xa (F.Xa) clotting time and thrombin time. These effects of FR-860 were weaker than that of UF-heparin. FR-860 showed equipotent efficacy on the anti-F.Xa activity, and weak antithrombin activity compared to UF-heparin. FR-860 had no effects on the activity of ATIII and fibrinolytic activity. UF-heparin shortened the urokinase-activated euglobulin lysis time and showed antiplasmin activity, but did not influence the activities of ATIII, plasminogen and alpha 2-plasmin inhibitor. UF-heparin decreased the fibrinogen level at higher doses. These efficacies of FR-860 were weaker than that of UF-heparin. These results suggest that FR-860 is more efficient and lower in bleeding risk than UF-heparin in clinical use.
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PMID:[Effects of low molecular weight heparin (FR-860) on coagulative and fibrinolytic activities]. 261 5

Plasminogen kringle 1+2+3 (K1-3) containing lysine-binding sites inhibited the reaction of plasmin with alpha 2-plasmin inhibitor (alpha 2PI), in a rate assay using a synthetic chromogenic substrate, S-2251. However, K1-3 did not inhibit the reaction to any degree between alpha 2PI and mini-plasmin which lacked the kringle 1 to 4 portion of plasmin. These results suggest that K1-3 blocked the binding of alpha 2PI to the lysine-binding site of plasmin. In the urokinase (UK)-induced fibrinolysis, K1-3 shortened the human plasma clot lysis time at low concentration (0.5-6 microM), and prolonged the lysis time at a high concentration (20 microM). Similar results were obtained in the lysis time of a fibrin clot consisting of plasminogen, fibrinogen and alpha 2PI isolated from human plasma. The kringle 4 (K4) of human plasminogen did not accelerate human plasma clot lysis at any concentration (1.2-24.1 microM). Furthermore, in the tissue plasminogen activator (TPA)-induced fibrinolysis, K1-3 also shortened both the lysis time of human plasma clot and fibrin clot as observed in UK-induced fibrinolysis, but K4 did not. The above findings indicate that the reaction of alpha 2PI with the lysine-binding site of plasmin is involved in the inhibition of plasmin activity by alpha 2PI, and in the presence of an inhibitor of this reaction, the balance of coagulofibrinolytic activity in plasma will be shifted towards the fibrinolytic side.
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PMID:Effects of kringles derived from human plasminogen on fibrinolysis in vitro. 282 51

The effects of intravenous urokinase administration were assessed in patients with acute myocardial infarction (AMI). Of 146 patients with AMI, 101 were admitted within 12 hours of onset of chest pain, and classified in four groups according to the method of administering urokinase. PTCR group (15 cases); PTCR was performed within six hours of onset, using less than 960,000 I.U.; Group A (20 cases); 1.5 million I.U. administered in one hour or 960,000 I.U. in 30 min; Group B (48 cases); 240,000 I.U. in two hours; and 4) Group C (18 cases); 240,000 I.U. in 12 hours. In groups A, B and C, urokinase was administered intravenously. The remaining 45 patients did not receive urokinase, and served as a control group. In the chronic stage, infarction-related coronary arteries were patent at rates of 93% in the PTCR group, 82% in group A, 76% in group B, 62% in group C, and 46% in the control group. In the PTCR group and in group A, alpha 2-plasmin inhibitor showed a steep decline to the lowest level on the day after urokinase administration, as did the summation of elevation of ST segments in conventional twelve-lead electrocardiograms. Peak CK times, which represent the duration (hours) from onset to the peak serum CK value increased in the following order: 13.3 +/- 4.8 in the PTCR group, 17.3 +/- 4.9 in group A, 17.3 +/- 6.9 in group B, 20.7 +/- 6.7 in group C and 22.5 +/- 6.4 in the control group. These data suggest early recanalization of occluded coronary arteries in the group A, and intravenous administration of high doses of urokinase in the early phase of AMI seemed to contribute to salvage the ischemic myocardium. However, assessment of ventricular wall motion by two-dimensional echocardiography failed to confirm appreciable improvement in the PTCR group and group A in comparison with the other groups.
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PMID:[The effects of intravenous urokinase administration in patients with acute myocardial infarction]. 295 26

Plasma levels of alpha 2-plasmin inhibitor (alpha 2PI), plasmin-alpha 2PI complex and cross-linked fibrin derivatives (XDP) were measured in 8 patients (12 episodes) with thromboembolic disorders on the initial administration of urokinase. In conjunction with a decrease in plasma alpha 2PI activity and antigen, plasmin-alpha 2PI complex increased following urokinase infusion in all cases except one who received a low dose (60,000 units) of urokinase. However, changes in XDP were variable among the patients. Plasma XDP level increased markedly in one, moderately in 4, slightly in one, and remained unchanged in 6 cases (episodes). The increment of plasma XDP correlated (r = 0.804, p = 0.003) with the dose of urokinase administered, but was independent of changes in plasmin-alpha 2PI complex. The plasma XDP elevation was associated with clinical improvement. These results suggest that simultaneous measurements of XDP and plasmin-alpha 2PI complex in plasma would be valuable for the pharmacological or hemostatic assessment of thrombolytic therapy.
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PMID:Evaluation of fibrinolytic therapy by measuring cross-linked fibrin derivatives and plasmin-alpha 2-plasmin inhibitor complex in plasma. 296 45


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