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)

Measurements were made of the nature and levels of plasminogen activator in human tears using, as a model of inflammation, patients undergoing cataract surgery. Tissue plasminogen activator (t-PA) but not urokinase plasminogen activator (u-PA) was found in tears. A wide variation in the range of t-PA in pre-operative tears was found. In those patients not receiving per-operative subconjunctival betamethasone a significant rise in t-PA was found in tears on the first post-operative day over pre-operative levels. A significant fall was noted in those receiving per-operative subconjunctival betamethasone.
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PMID:Plasminogen activator in human tears. 128 46

The concentrations of tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA) and plasminogen activator inhibitor (PAI-1) have been determined in endometrial curettings obtained from 46 subfertile women during proliferative, early or late secretory phases of the menstrual cycle. t-PA activity and antigen concentrations was significantly higher (P < 0.001) in late secretory endometrium than in proliferative or early secretory endometrium. Higher concentrations of PAI-1 antigen (P < 0.05) were also noted in late secretory phase than in proliferative and early secretory endometrium. However, u-PA concentration was not significantly different and no PAI activity could be demonstrated in the menstrual phases studied. Zymography studies confirmed the presence of both t-PA and u-PA in the endometrium. Ovarian hormonal patterns may therefore influence the activity of plasminogen activators especially of t-PA in the endometrium during various phases of the menstrual cycle.
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PMID:Concentration of plasminogen activators and inhibitor in the human endometrium at different phases of the menstrual cycle. 133 23

Tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA) and plasminogen activator inhibitors (PAI) are elevated in late pregnancy with t-PA and u-PA remaining so at 6 weeks postnatal. PAI-2 remains at postpartum but was absent by 6 weeks postnatal unlike PAI activity which was absent at postpartum and returned to nonpregnant level at postnatal. The potential fibrinolytic response to stress is much reduced in pregnancy thus increasing the risk of thromboembolism.
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PMID:Plasminogen activators and inhibitors in normal late pregnancy, postpartum and in the postnatal period. 134 96

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

Regulation of the activity of proteolytic enzymes is of major importance in the turnover of connective tissues. The search for physiologically relevant activation mechanisms of principal tissue-degrading enzymes, e.g., metalloproteinases, has therefore been of wide interest. We have now studied whether the initiating factor of the fibrinolytic system, urokinase plasminogen activator (u-PA), may also function in the early steps of activation of one of the metalloproteinases, the M(r) 72,000 gelatinase/type IV collagenase produced by cultured fibroblasts. Treatment of the secreted M(r) 72,000 proteinase by u-PA yielded a cleavage product of M(r) 62,000 as revealed by fluorography of radioactively labeled proteins as well as by gelatin zymography SDS-PAGE gels. The u-PA-catalyzed cleavage of the M(r) 72,000 proteinase was blocked by anti-u-PA antibodies, but was unaffected by the plasmin inhibitor aprotinin, thus indicating a specific action for the activator. On the contrary, the tissue activator of plasminogen, t-PA, did not cleave the type IV collagenase in similar assays. u-PA-catalyzed cleavage of recombinant type IV collagenase, produced in a baculovirus expression system, yielded a similar M(r) 62,000 activity in gelatinolysis assay. Zymograms of the isolated pericellular matrices of cultured fibroblasts also revealed M(r) 72,000 gelatinolytic polypeptide that was converted to an M(r) 62,000 form by u-PA. Both polypeptides were recognized in immunoblotting by antibodies against the gelatinase/type IV collagenase, suggesting immunological identity with the secreted enzyme. Thus the M(r) 72,000 gelatinase/type IV collagenase is not only secreted, but also deposited into the pericellular fibroblast matrix, and both forms are substrates for u-PA. The results suggest a new potential role for u-PA as a direct regulator of metalloproteinase-mediated extracellular proteolysis via the cleavage of the M(r) 72,000 gelatinase/type IV collagenase to an M(r) 62,000 form.
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PMID:Proteolytic processing of the 72,000-Da type IV collagenase by urokinase plasminogen activator. 139 99

A mutant single chain urokinase plasminogen activator (scu-PA) was constructed by the addition of an apical membrane targeting signal from decay accelerating factor to the scu-PA carboxyl terminus. Bovine aortic endothelial cells (EC) were transduced with the mutant scu-PA. Metabolic labeling, immunoprecipitation, and gel electrophoresis revealed that the mutant scu-PA was present in a single-chain form at the EC surface. Immunohistochemistry and enzyme-linked immunosorbent assay before and after treatment of EC with phosphotidylinositol-specific phospholipase C confirmed that scu-PA was attached to the EC surface by a glycosyl-phosphotidylinositol anchor. Approximately 10(6) anchored scu-PA molecules/cell were present; however, anchoring was not 100% efficient, with scu-PA released into the medium as well. Selective biotinylation of the apical and basolateral surfaces revealed that anchored scu-PA was polarized to the apical surface. Apically anchored scu-PA could be converted by plasmin to two-chain urokinase, with a normal specific activity (140,000 IU/mg) as measured with the chromogenic substrate S-2444. Expression of anchored scu-PA resulted in an increase in EC surface plasminogen activator activity, as compared with the activity of either untransduced EC or EC transduced with a wild type scu-PA. These experiments demonstrate: 1) apical membrane targeting can be accomplished in EC; 2) scu-PA can be anchored to the EC surface with preservation of enzymatic activity; 3) EC surface plasminogen activator activity is significantly increased by the presence of anchored scu-PA. Cell surface targeted plasminogen activators may eventually be useful in the prevention and treatment of intravascular thrombosis.
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PMID:Expression of an anchored urokinase in the apical endothelial cell membrane. Preservation of enzymatic activity and enhancement of cell surface plasminogen activation. 153 28

Enzymatic properties of phosphorylated urokinase plasminogen activator (P-uPA) (1) extracted from human carcinomatous cell line Detroit 562 cells were compared with those of non-phosphorylated uPA of urinary origin (nP-uPA). Using plasminogen as a substrate, the Km and Kcat of P-uPA were higher than that of nP-uPA while the Kcat/Km was lower. By zymography, a greater degree of plasminogen activation was observed. Concanavalin A reacted to both the enzymes. P-uPA had a low affinity for the inhibitors of plasminogen activator PAI-1 and PAI-2, and was inhibited only by the excess amounts of inhibitors. For PAI-1, and the KIs of P-uPA was greater and for PAI-2, KI was higher for P-uPA. These alterations by phosphorylation enable uPA to be more efficient in a focal proteolysis through plasminogen activation.
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PMID:Enzymatic properties of the phosphorylated urokinase-type plasminogen activator isolated from a human carcinomatous cell line. 154 Jan 90

The effect of therapeutic and pharmacological concentrations of tiaprofenic acid, a non-steroidal anti-inflammatory drug (NSAID), on the synthesis of the plasminogen activators, urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA), and the plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2), by human synovial membranes isolated from osteoarthritis (OA) and rheumatoid arthritis (RA) sufferers was evaluated. Both forms of plasminogen activator (PA) and PA inhibitor (PAI) were synthesized by the arthritic synovium. PAI-1 and PAI-2 were both synthesized in greater amounts than the plasminogen activators. Tiaprofenic acid induced a dose-dependent decrease in uPA synthesis in both OA and RA, particularly in OA synovium, but had no true effect on tPA. Tiaprofenic acid also exerted a suppressive effect on the synthesis of PAI-1 in both OA and RA synovial membranes, and on the release of PAI-2 in RA synovium. The results of this study indicate that a decrease in uPA synthesis may be one of the mechanisms by which tiaprofenic acid could exert its effects on the arthritic process. The suppressive action of tiaprofenic acid on PAI is not likely to have a significant impact on the balance of plasminogen activators and plasminogen activator inhibitors, as plasminogen activator inhibitors are synthesized in greater amounts than plasminogen activators.
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PMID:Effects of tiaprofenic acid on plasminogen activators and inhibitors in human OA and RA synovium. 155 50

Thrombolytic therapy for evolving acute myocardial infarction (AMI) reduces infarct size, preserves ventricular function, and reduces mortality. Intravenous streptokinase is commonly followed by approximately 50% patency of coronary arteries within 90 minutes and by reduction of mortality by 25%. Recombinant tissue plasminogen activator (rt-PA) is more potent for coronary arterial thrombolysis, producing both more rapid and more frequent recanalization (approximately 75% patency at 90 minutes) with a dose of 100 mg given over 3 hours. Side effects (mainly bleeding) associated with the use of streptokinase and rt-PA are not markedly different. That the higher efficacy of rt-PA would translate into a larger reduction of mortality is suggested by the results of several small trials but remains to be confirmed in well-designed comparative clinical trials. This question has not been adequately answered by the recent International rt-PA/streptokinase mortality trial and the International Study on Infarct Survival (ISIS-3) study, because of concerns with respect to the role of conjunctive intravenous heparin administration and the dose of rt-PA used in ISIS-3. All available thrombolytic agents still have significant shortcomings, including the need for large doses to be maximally efficient, a limited fibrin specificity, and a significant associated bleeding tendency. New developments toward improved efficacy and fibrin-specificity of thrombolytic agents include the use of mutants of rt-PA, chimeric rt-PA or single chain urokinase plasminogen activator molecules, and antibody-targeted thrombolytic agents. Some of these artificial plasminogen activators have a 5- to 10-fold increased potency (thrombolytic activity per unit dose), but whether they are safe enough to be clinically useful remains to be established. The conjunctive use of anticoagulants and antiplatelet agents with thrombolytic agents increases their efficacy to an extent that monotherapy with a plasminogen activator alone is no longer tenable. Heparin and aspirin are only moderately efficient for acceleration of lysis and prevention of reocclusion, but are relatively safe. More selective thrombin inhibitors and antiplatelet agents are more potent, but their safety remains to be confirmed. Continued investigation in this area will provide new insights and promote progress toward the development of the ideal thrombolytic therapy, characterized by maximized stable coronary arterial thrombolysis with minimal bleeding.
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PMID:Designing thrombolytic agents: focus on safety and efficacy. 172 81

An experimental cerebral embolic model was prepared by an injection of [125I]fibrin clot particles (20-100 microns) into the left internal carotid artery in rats, and the changes in radioactivity of the brain were continuously monitored by a gamma-ray detector. The autoradiograms of the caput transections showed the existence of emboli in small vessels of the left hemicerebrum. After the injection of [125I]fibrin clots, the radioactivity spontaneously decreased to a half of the initial radioactivity at 90 min. The decrease in radioactivity which represented the embolus dissolution was markedly suppressed by an antiplasmin agent, trans-4-aminomethyl cyclohexane carboxylic acid, indicating that the endogenous fibrinolysis through the activation of plasminogen is generated in the cerebral small vessels after the embolization. Consecutive injection of fibrin clots caused a summation of the radioactivity and decreased the rate of dissolution at every embolus preparation. The thrombolytic agents were infused via the left internal carotid artery for 30 min after the second successive injection of fibrin clots. Although the spontaneous dissolution of emboli was observed during the infusion of saline, tissue plasminogen activator (t-PA) as well as urokinase plasminogen activator (u-PA) produced a further dissolution. Approximately half of the emboli disappeared 60 min after the infusion of t-PA at a dose of 75 micrograms/kg and at a dose of 10000 IU/kg, respectively.
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PMID:Thrombolytic effect of tissue plasminogen activator in a cerebral embolic model. 180 87


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