Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Beta2-glycoprotein I (beta2GPI) is a glycoprotein of unknown physiological function. It is the main target antigen for antiphospholipid antibodies in patients with antiphospholipid syndrome (APS). beta2GPI binds with high affinity to the atherogenic lipoprotein Lp(a) which shares structural homology with plasminogen, a key molecule in the fibrinolytic system. Impaired fibrinolysis has been described in APS. The present work reports the interaction between beta2GPI and Glu-Plasminogen which may explain the recently described proteolytic effect of plasmin on beta2GPI. In the process of Glu-Plasminogen activation, we found an increase in plasmin generation both at fibrin and cellular surface level as a function of the concentration of beta2GPI added, suggesting an important role as a cofactor in the trimolecular complex beta2GPI-Plasminogen-tPA. This phenomenon represents a novel regulatory step both in the positive feedback mechanism for extrinsic fibrinolysis and in antithrombotic regulation. IgG anti-beta2GPI antibodies recognized the beta2GPI at the endothelial surface inducing its activation with an increase of ICAM-I and a decrease in the expression of thrombomodulin favoring a pro-thrombotic state in the vascular endothelium. The interference in the plasmin conversion by anti-beta2GPI antibodies could generate thrombosis as observed in APS.
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PMID:The role of beta2-glycoprotein I (beta2GPI) in the activation of plasminogen. 1648 Sep 36

When the continuity of the vascular endothelium is disrupted, platelets and fibrin seal off the defect. Haemostatic processes are classified as primary (mainly involving platelets) and secondary (mainly related to fibrin formation or blood coagulation). When the blood clot is no longer required for haemostasis, the fibrinolytic system will dissolve it. The pivotal ligand for initial platelet recruitment to injured vessel wall components is von Willebrand factor (vWF), a multimeric protein present in the subendothelium and in plasma, where it is conformationally activated by shear forces. Adhering activated platelets recruit additional platelets, which are in turn activated and form a platelet aggregate. Coagulation is initiated by a reaction, activating factors IX and X. Once critical amounts of factor Xa are generated, thrombin generation is initiated and soluble fibrinogen is converted into insoluble fibrin. Excessive thrombin generation is prevented via inhibition by antithrombin and also via downregulation of its further generation by activation of the protein C pathway. Activation of the fibrinolytic system results from conversion of the proenzyme plasminogen into the active serine proteinase plasmin by tissue-type or urokinase-type plasminogen activators. Plasmin digests the fibrin component of a blood clot. Inhibition of the fibrinolytic system occurs at the level of the plasminogen activator (by plasminogen activator inhibitors) or at the level of plasmin (by alpha2-antiplasmin). Together, these physiological processes act to maintain normal functioning blood vessels and a non-thrombotic state.
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PMID:Haemostasis. 1700 71

An important feature of chemokines is their ability to bind to the glycosaminoglycan (GAG) side chains of proteoglycans, predominately heparin and heparan sulfate. To date, all chemokines tested bind to immobilized heparin in vitro, as well as cell surface heparan sulfate in vitro and in vivo. These interactions play an important role in modulating the action of chemokines by facilitating the formation of stable chemokine gradients within the vascular endothelium and directing leukocyte migration, by protecting chemokines from proteolysis, by inducing chemokine oligomerization, and by facilitating transcytosis. Despite the importance of eotaxin in eosinophil differentiation and recruitment being well established, little is known about the interaction between eotaxin and GAGs and the functional consequences of such an interaction. Here we report that eotaxin binds selectively to immobilized heparin with high affinity (K(d) = 1.23 x 10(-8) M), but not to heparan sulfate or a range of other GAGs. The interaction of eotaxin with heparin does not promote eotaxin oligomerization but protects eotaxin from proteolysis directly by plasmin and indirectly by cathepsin G and elastase. In vivo, co-administration of eotaxin and heparin is able to significantly enhance eotaxin-mediated eosinophil recruitment in a mouse air-pouch model. Furthermore, when heparin is co-administered with eotaxin at a concentration that does not normally result in eosinophil infiltration, eosinophil recruitment occurs. In contrast, heparin does not enhance eotaxin-mediated eosinophil chemotaxis in vitro, suggesting protease protection or haptotactic gradient formation as the mechanism by which heparin enhances eotaxin action in vivo. These results suggest a role for mast cell-derived heparin in the recruitment of eosinophils, reinforcing Th2 polarization of inflammatory responses.
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PMID:Eotaxin selectively binds heparin. An interaction that protects eotaxin from proteolysis and potentiates chemotactic activity in vivo. 1738 13

Loss of vascular barrier function causes leak of fluid and proteins into tissues, extensive leak leads to shock and death. Barriers are largely formed by endothelial cell-cell contacts built up by VE-cadherin and are under the control of RhoGTPases. Here we show that a natural plasmin digest product of fibrin, peptide Bbeta15-42 (also called FX06), significantly reduces vascular leak and mortality in animal models for Dengue shock syndrome. The ability of Bbeta15-42 to preserve endothelial barriers is confirmed in rats i.v.-injected with LPS. In endothelial cells, Bbeta15-42 prevents thrombin-induced stress fiber formation, myosin light chain phosphorylation and RhoA activation. The molecular key for the protective effect of Bbeta15-42 is the src kinase Fyn, which associates with VE-cadherin-containing junctions. Following exposure to Bbeta15-42 Fyn dissociates from VE-cadherin and associates with p190RhoGAP, a known antagonists of RhoA activation. The role of Fyn in transducing effects of Bbeta15-42 is confirmed in Fyn(-/-) mice, where the peptide is unable to reduce LPS-induced lung edema, whereas in wild type littermates the peptide significantly reduces leak. Our results demonstrate a novel function for Bbeta15-42. Formerly mainly considered as a degradation product occurring after fibrin inactivation, it has now to be considered as a signaling molecule. It stabilizes endothelial barriers and thus could be an attractive adjuvant in the treatment of shock.
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PMID:Peptide Bbeta(15-42) preserves endothelial barrier function in shock. 1940 65

Dirofilaria immitis is the causative agent of canine and feline heartworm disease. The parasite can survive for long periods of time (7 years or more) in the circulatory system of immunocompetent reservoirs, producing usually a chronic inflammatory vascular disease. In addition, the simultaneous death of groups of adult worms can trigger an acute disease characterized by the exacerbation of inflammatory reactions and the emergence of serious thromboembolic events. In the context of the D. immitis/host relationships, the aim of this study was to investigate the interaction between the excretory/secretory antigens from D. immitis adult worms (DiES) and the fibrinolytic system of the host. Using an enzyme-linked immunosorbent assay we showed that DiES extract is able to bind plasminogen and generate plasmin, although this fact requires the presence of the tissue plasminogen activator (t-PA). Moreover, we established that DiES extract enhances t-PA expression in cultured vascular endothelial cells. Additionally, 10 plasminogen-binding proteins from DiES extract were identified by mass spectrometry (HSP60, actin-1/3, actin, actin 4, transglutaminase, GAPDH, Ov87, LOAG_14743, galectin and P22U). The data suggest that DiES antigens interact with the environment of the parasite regulating the activation of the fibrinolytic system of the host with involvement of the vascular endothelium in the process.
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PMID:Excretory/secretory antigens from Dirofilaria immitis adult worms interact with the host fibrinolytic system involving the vascular endothelium. 2205 Sep 27

Thrombus formation remains a serious problem in developing blood compatible materials. Despite continuous, intensive efforts over many years to prepare surfaces that prevent clotting, such surfaces have not been achieved; indeed it seems that surface-induced clotting is inevitable. An alternative approach is to accept that clotting will occur and to design surfaces so that small, nascent clots will be lysed before they can cause harm. The generation of plasmin, as in the fibrinolytic system, may be adopted for this purpose. The vascular endothelium (the inner surface of intact blood vessels) releases nitric oxide (NO) on a continuous basis. NO protects against platelet activation and aggregation, and also has an anti-proliferative effect on smooth muscle cells (SMCs). Based on these two important functions of the vascular system, the approach of constructing a fibrinolytic surface that generates NO is developed in the present work. Poly(oligo(ethylene glycol) methyl ether methacrylate-co-6-amino-2-(2-methacylamido)-hexanoic acid) (poly(OEGMA-co-LysMA)) was attached to a vinyl-functionalized polyurethane (PU) surface by graft polymerization giving a surface (PU-POL) with protein-resistant properties (via poly(OEGMA)) and clot lysing properties (via poly(LysMA)). Selenocystamine, which catalyzes S-nitrosothiol decomposition to generate NO in the vasculature, was then immobilized on the PU-POL surface via covalent attachment. A dual functioning surface with fibrinolytic activity (lysis of nascent clots) and NO releasing ability (inhibition of platelet adhesion and SMC adhesion as well as proliferation) was thereby constructed.
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PMID:A hemocompatible polyurethane surface having dual fibrinolytic and nitric oxide generating functions. 3226 76


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