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:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cells play a critical role in thromboregulation by controlling the assembly of fibrinolytic constituents on the membrane. The assembly system illustrated in FIGURE 6 is characterized by the binding of circulating glu-plasminogen to a membrane receptor (Pathway 1). A membrane-associated protease (possibly plasmin) converts the inactive zymogen into a catalytically more efficient zymogen lys-plasminogen (Pathway 2). T-PA binds to a specific receptor, retains its catalytic activity, and is protected from its natural inhibitor PAI-1. The membrane provides a favorable environment for plasmin generation (Pathway 3) at the vessel surface and contributes to the maintenance of a physiological nonthrombogenic state. The immobilization and surface activation of plasminogen provides an important mechanism for localizing proteolytic activity at the surface of other cells such as macrophages and tumor cells. Lp(a), a plasminogen-like lipoprotein, by competing at the endothelial surface for plasminogen binding down-regulates endothelial cell plasmin generation and may thus promote localized thrombogenesis that over a period of time contributes to progressive atherosclerosis.
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PMID:Endothelial cell fibrinolytic assembly. 190 39

The levels of hemostatic and fibrinolytic parameters and of molecular markers in venous blood before and after 10 minutes of venous occlusion were measured to evaluate vascular endothelial function in 36 patients with old myocardial infarction, and also in 20 healthy subjects. T-PA activity in the venous blood after occlusion was significantly lower in the patient group compared with the control group, and was lowest in patients with diabetes mellitus. These results were considered to be attributable to elevated PAI-1 and alpha 2 PI levels in these patients. The mean levels of t-PA antigen and VIII R: Ag in venous blood before occlusion were significantly higher in the patient group, but the mean amount of release was no higher in patients than in controls. The plasmin.alpha 2PI complex levels before venous occlusion seemed to indicate the presence of secondary fibrinolysis accompanying hypercoagulability, and the level was significantly higher in patients with diabetes mellitus. Venous occlusion induced the release of t-PA and VIII R: Ag without causing a significant difference in the mean amount of increase of these substances in patient and control groups. However, the lower level of t-PA activity after venous occlusion together with the higher levels of VIII: C, VIII R: Ag, alpha 2PI, PAI-1, and plasmin.alpha 2PI complex before venous occlusion in the patients, indicated that the patient group was in a hypercoagulable and hypofibrinolytic state. In those with diabetes mellitus, the changes were more significant.
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PMID:[Changes induced by venous occlusion in coagulation and fibrinolysis in patients with old myocardial infarction]. 202 72

The role of the actin microfilaments in maintaining the integrity of the monolayer and activating endothelial repair processes is not well understood. This study was designed to characterize the prominent changes in F-actin distribution in endothelial cells that are associated with shape changes in the cells after perturbation of a confluent monolayer. F-actin was localized by using rhodamine phalloidin and fluorescence microscopy. The dense peripheral band (DPB) and vinculin cell-cell junctions were co-localized by using double fluorescence and immunofluorescence microscopy. Thrombin and 12-o-tetradecanoyl-myristyl-13-acetate (TPA) caused loss of the DPB and an increase in the central microfilament bundles, while agents that caused rounding of the cells (including plasmin, trypsin, and chymotrypsin) did not cause loss of the DPB although large gaps were formed between cells. The thrombin and TPA effects were rapid and reversible and were associated with an accompanying loss of vinculin cell-cell plaques. The mechanisms of the effects were not studied. It was postulated that thrombin and TPA were activating endothelial repair processes.
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PMID:Endothelial monolayer integrity. Perturbation of F-actin filaments and the dense peripheral band-vinculin network. 213 94

The lipoprotein Lp(a) is a cholesterol-rich plasma lipoprotein from the density fraction 1.06-1.21 g/ml. Numerous clinical and epidemiological studies have revealed a strong correlation between high plasma Lp(a) concentrations and the incidence of coronary heart disease. Furthermore, the Lp(a)-specific protein apo(a) has been detected in atherosclerotic lesions. Lp(a) is essentially an LDL-like lipoprotein particle to which the glycoprotein apo(a) is attached through a disulfide bridge with apo B-100. The elucidation of the amino acid sequence of apo(a) revealed a high homology to specific regions of human plasminogen. The latter consists of five tandemly arranged kringle domains followed by a C-terminal trypsin-like protease region. Apo(a) is composed of a large number of kringle domains, all highly homologous to kringle IV of plasminogen, followed by a kringle V-like protease-domain. The lipoprotein Lp(a), therefore, combines structural elements of both the lipoprotein and coagulation systems. In contrast to plasminogen, Lp(a) cannot be activated by TPA, streptokinase or urokinase to give proteolytic activity. However, in vitro studies have shown that Lp(a) can both inhibit endothelial cell induced fibrinolysis and can also bind to plasmin modified fibrin. These findings provide a pathobiochemical basis for the involvement of Lp(a) in atherosclerotic and thrombotic processes. The function of this lipoprotein is, however, still unclear.
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PMID:[Lipoprotein(a): characteristics of a special lipoprotein and its potential clinical significance]. 214 32

Cultured human endothelial cells synthesize and secrete two types of plasminogen activator, tissue plasminogen activator (t-PA) and urokinase (u-PA). Previous work from this laboratory (Hajjar, K.A., Hamel, N. M., Harpel, P. C., and Nachman, R. L. (1987) J. Clin. Invest. 80, 1712-1719) has demonstrated dose-dependent, saturable, and high affinity binding of t-PA to two sites associated with cultural endothelial cell monolayers. We now report that an isolated plasma membrane-enriched endothelial cell fraction specifically binds 125I-t-PA at a single saturable site (Kd 9.1 nM; Bmax 3.1 pmol/mg membrane protein). Ligand blotting experiments demonstrated that both single and double-chain t-PA specifically bound to a Mr 40,000 membrane protein present in detergent extracts of isolated membranes, while high molecular weight, low molecular weight, and single-chain u-PA associated with a Mr 48,000 protein. Both binding interactions were reversible and cell-specific and were inhibitable by pretreatment of intact cells with nanomolar concentrations of trypsin. The relevant binding proteins were not found in subendothelial cell matrix, failed to react with antibodies to plasminogen activator inhibitor type 1 and interacted with their respective ligands in an active site-independent manner. The isolated t-PA binding site was resistant to reduction and preserved the capacity for plasmin generation. In contrast, the isolated u-PA binding protein was sensitive to reduction, and did not maintain the catalytic activity of the ligand on the blot. The results suggest that in addition to sharing a matrix-associated binding site (plasminogen activator inhibitor type 1), both t-PA and u-PA have unique membrane binding sites which may regulate their function. The results also provide further support for the hypothesis that plasminogen and t-PA can assemble on the endothelial cell surface in a manner which enhances cell surface generation of plasmin.
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PMID:Identification and characterization of human endothelial cell membrane binding sites for tissue plasminogen activator and urokinase. 215 65

The effects of exogenously added urokinase type plasminogen activator, tissue type plasminogen activator, plasmin and thrombin on the proliferation of primary cultures of cells derived from prostatic hyperplasia or prostatic carcinomas were investigated by measuring the incorporation of 3H-thymidine into the cultures. Addition of urokinase type plasminogen activator (1.35 x 10(-9) M) or thrombin (10(-7) M) to the culture medium caused a two-fold increase of 3H-thymidine incorporation, regardless of the origin of the prostatic cells. Tissue type plasminogen activator did not alter the rate of 3H-thymidine incorporation, whereas plasmin caused a 25% decrease of 3H-thymidine incorporation in all cultures.
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PMID:Effect of urokinase on the proliferation of primary cultures of human prostatic cells. 244 91

Bovine serum albumins (BSA), modified with a variety of carboxyl group agents, stimulated the tissue-type plasminogen activator (t-PA)-catalyzed activation of human plasminogen. Modification with taurine (tau) and putrescine (put) provided the best stimulants. The tauBSA and putBSA were effective at a concentration of 5 micrograms/ml and enhanced the Lys-plasminogen activation by two-chain t-PA in a dose-dependent manner to a maximum of 44- to 46-fold at 200 micrograms/ml. The Km values for the activation of Glu-plasminogen by t-PA in the presence of tauBSA and putBSA (100 micrograms/ml) were 1.7 and 1.8 microM, while the kcat values were 0.059 and 0.062 s-1, respectively. T-PA was bound to both tauBSA and putBSA, which were immobilized on agarose beads, with KD values of 163 and 138 nM, respectively. The two modified BSAs were good substrates for plasmin and were hydrolyzed by the enzyme to small peptides. All of these modified BSA-related actions were inhibited by lysine analogs (e.g. tranexamic acid) which were adjusted to the concentrations required for the inhibition of the plasminogen (Kringle 1 domain) binding to fibrin. On the other hand, acetylation or succinylation of the amino groups of BSA was not effective, while alkylation of the thiol groups of this protein resulted in a moderate stimulation of the plasmin generation. The present results show that t-PA and plasminogen form complexes with certain charge-modified BSAs via their lysine-binding sites. The different stimulation potency of modified BSAs may provide a model for in vivo counterparts of fibrin.
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PMID:A comparison of bovine serum albumins, modified with a variety of carboxyl group agents, as stimulators of tissue-type plasminogen activator-catalyzed activation of plasminogen. 250 19

Thrombospondin (TSP) is a multifunctional platelet alpha-granule and extracellular matrix glycoprotein that binds specifically to plasminogen (Plg) via that protein's lysine-binding site and modulates activation by tissue activator (TPA). In this study we report that the plasminogen activators, TPA and urokinase, greatly influence the binding of Plg to TSP. Using an enzyme-linked immunosorbent assay and a TSP-Sepharose affinity bead-binding assay we have found that Plg-TSP complex formation was markedly enhanced (up to 5-fold) when catalytic concentrations of Plg activators were included in the reaction mixtures. The enhancement was dependent upon the generation of small amounts of active plasmin and was duplicated by pretreatment of the immobilized TSP with plasmin prior to addition of the Plg. The enhancement effect was associated with selective proteolysis of the immobilized TSP. Purified Lys-Plg (the plasmin modified form of native Glu-Plg) bound to TSP to a greater extent than Glu-Plg, and binding of both forms was augmented by Plg activators. The apparent KD values of complex formation were unchanged in the presence of Plg activators suggesting that the enhancement effect was due to the generation of additional binding sites. The increased amount of bound Plg was demonstrated to result in a similar increase in the amount of plasmin generated from the complexes by TPA. Plg activators did not influence binding of Plg to histidine-rich glycoprotein or of histidine-rich glycoprotein to TSP, demonstrating specificity. In addition when TSP was treated with other proteases (human thrombin or human leukocyte elastase) no augmentation of Plg binding was seen. Thus, the initial production of small amounts of plasmin from Plg immobilized on TSP in fibrin-free microenvironments could generate a positive feedback loop by enzymatically modifying both TSP and Plg, resulting in an increase in TSP-Plg complex formation leading to the localized production of substantially more plasmin.
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PMID:Tissue plasminogen activator and urokinase enhance the binding of plasminogen to thrombospondin. 294 36

Tissue plasminogen activator (t-PA) purified from culture of human lung cells was infused over 30 min at the dose of 7.2 mg or 14.4 mg per person into human male volunteers. T-PA declined rapidly after the cessation of infusion with T1/2, alpha of about 4 min and T1/2, beta of about 40 min. The plasma fibrinogen and plasminogen did not change during and after the infusion of t-PA. The concentration of alpha 2antiplasmin (alpha 2AP) did not change but that of alpha 2AP-plasmin complex increased to about 200 nM at the infusion of 14.4 mg/person. Fragment D was hardly found at the infusion of 7.2 mg but some increase in the concentration of D was observed at the infusion of 14.4 mg. The concentration of free plasminogen activator inhibitor (PAI-1) rapidly declined and kept low up to 150 min, and returned to normal the following day. The concentration of t-PA-PAI-1 complex increased rapidly, and slowly declined after the end of the infusion of t-PA, suggesting no significant release of PAI-1 in response to increase in plasma concentration of t-PA or t-PA-PAI-1 complex. The addition of thrombin to the blood after withdrawal resulted in the significant formation of D-dimer, even at 150 min after the infusion. There was not hyperaggregability of platelets during and after the infusion of t-PA. These results suggest that the infusion of t-PA at the dose of 7.2 mg or 14.4 mg/person for 30 min resulted in high fibrinolytic potential in the blood without the breakdown of fibrinogen or increase in PAI-1.
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PMID:Changes in various parameters of fibrinolysis in persons infused with tissue plasminogen activator: special reference to plasminogen activator inhibitor. 314 66

Endothelial cells are known to release the two major forms of plasminogen activator, tissue plasminogen activator (TPA) and urokinase. We have previously demonstrated that plasminogen (PLG) immobilized on various surfaces forms a substrate for efficient conversion to plasmin by TPA (Silverstein, R. L., Nachman, R. L., Leung, L. L. K., and Harpel, P. C. (1985) J. Biol. Chem. 260, 10346-10352). We now report the binding of human PLG to cultured human umbilical vein endothelial cell (HUVEC) monolayers, utilizing a newly devised cell monolayer enzyme-linked immunosorbent assay system. PLG binding to HUVEC was concentration dependent and saturable at physiologic PLG concentration (2 microM). Binding of PLG was 70-80% inhibited by 10 mM epsilon-aminocaproic acid, suggesting that it is largely mediated by the lysine-binding sites of PLG. PLG bound at an intermediate level to human fibroblasts, poorly to human smooth muscle cells, and not at all to bovine smooth muscle or bovine endothelial cells; unrelated proteins such as human albumin and IgG failed to bind HUVEC. PLG binding to HUVEC was rapid, reaching a steady state within 20 min, and quickly reversible. 125I-PLG bound to HUVEC with an estimated Kd of 310 +/- 235 nM (S.E.); each cell contained 1,400,000 +/- 1,000,000 (S.E.) binding sites. Functional studies demonstrated that HUVEC-bound PLG is activatable by TPA according to Michaelis-Menten kinetics (Km, 5.9 nM). Importantly, surface-bound PLG was activated with a 12.7-fold greater catalytic efficiency than fluid phase PLG. These results indicate that PLG binds to HUVEC in a specific and functional manner. Binding of PLG to endothelial cells may play a pivotal role in modulating thrombotic events at the vessel surface.
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PMID:Binding of plasminogen to cultured human endothelial cells. 374 61


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