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)

Angiogenesis, the formation of new blood vessels from existing vessels, plays an important role during development. In the adult, it is limited to the female reproductive system and to tissue repair and pathological conditions. Repair associated angiogenesis is usually accompanied by the presence of inflammatory cells, vascular leakage, and fibrin deposition. The temporary fibrin matrix acts, not only as a sealing matrix, but also as a scaffolding for invading leukocytes and endothelial cells during tissue repair. We have used a three-dimensional fibrin matrix to study the outgrowth of human microvascular endothelial cells in capillary-like tubular structures. This process is induced by the simultaneous addition of an angiogenic growth factor (bFGF or VEGF) and the cytokine TNF alpha, and is enhanced by hypoxia. It involves proteolytic activities, in particular cell bound urokinase/plasmin and matrix metalloproteinase activities. Modulation of the fibrin structure markedly affects the extent and stability of capillary tube formation in vitro. Preparation of fibrin at different pH (7.0-7.8) or crosslinking of the fibrin matrix induces differences in fibrin matrix rigidity and structure. This is accompanied by a change in capillary ingrowth. Heparins, in particular low molecular weight heparins, modulate the fibrin structure and by this action affect angiogenesis in vitro. A mutant fibrinogenNieuwegein, which lacks the terminal part of the A alpha chain of fibrin harboring an RGD sequence and the transglutaminase sequence, provided additional evidence that the structure of fibrin is an important determinant for angiogenesis. These findings may have impact on improving wound healing and on influencing angiogenesis in malignancies with a fibrinous stroma.
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PMID:Role of fibrin matrix in angiogenesis. 1146 Apr 96

Change in fibrin stabilizing activity of factor XIII A subunit (FXIII-A) caused by a specific mutation, Val34Leu, is recently implicated to incidences of pathophysiology of thrombosis. In an effort to understand the effect of Val34Leu on enhanced catalytic role of FXIII-A, wild type human factor XIII A (HFXIII-A) and mutant HFXIII-A: HFXIII-A (V34L), HFXIII-A (V35L) and HFXIII-A (V34L/V35L) cDNA were expressed in E.coli system where the purified recombinant FXIII-A (gammaFXIII-A) showed a similar specific transglutaminase activity comparable to the human native FXIII-A from platelet. Using these gammaFXIII-A mutants, the activation kinetics by thrombin and the enzymatic properties of the activated gammaFXIII-A were characterized. gammaFXIII-A (V34L) and gammaFXIII-A (V34L/V35L) mutants were activated by thrombin much faster than those of wild type gammagFXIII-A and V35L variant. However, the activated gammaFXIII-A and mutants showed the identical catalytic efficiency as measured by in vitro assay. These results suggest that ready activation caused by a specific mutation of neighboring thrombin cleavage site(s) in the activation peptide of FXIII-A like V34L resulted in the real-time amount of the activated factor XIII-A that could influence the outcome of fibrin stabilization in vivo such as alpha2-plasmin inhibitor crosslinking to fibrin, a reaction known to be dependent on the initial concentration of active factor-XIII-A.
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PMID:Effects of Val34Leu and Val35Leu polymorphism on the enzyme activity of the coagulation factor XIII-A. 1252 4

Transforming growth factor-beta (TGF-beta) is secreted in a latent form; thus, activation is critical for the control of TGF-beta action. Latent TGF-beta exists in a complex in which mature TGF-beta is noncovalently linked to latency associated peptide (LAP) and latent TGF-beta binding protein (LTBP) complex. We have shown that latent TGF-beta is efficiently activated in heterotypic cultures of endothelial cells (ECs) and smooth muscle cells (SMCs). Under those conditions, LAP plays an important role in targeting latent TGF-beta to the surface of SMCs, and plasmin and calpain target it to the surface of ECs for activation. Here, we demonstrate in a homotypic culture system that fragments of LAP increase the binding of latent TGF-beta to ECs, resulting in its activation by cell-associated proteolysis. LAP fragments appear to bind to the cell surface and augment the binding of latent TGF-beta, independent of transglutaminase. These results suggest a unique mechanism for the activation of latent TGF-beta by proteolytic fragments of LAP. The mechanism may arise from degradation by elevated levels of proteases under certain conditions.
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PMID:Augmented binding and activation of latent transforming growth factor-beta by a tryptic fragment of latency associated peptide. 1290 58

Most growth factors naturally involved in development and regeneration demonstrate strong binding to the extracellular matrix and are retained there until being locally mobilized by cells. In spite of this feedback between cell activity and growth factor mobilization in the extracellular matrix, this approach has not been extensively explored in therapeutic situations. We present an engineered bone morphogenetic protein-2 (BMP-2) fusion protein that mimics such function in a surgically relevant matrix, fibrin, incorporated into the matrix until it is locally liberated by cell surface-associated proteases. A tripartite fusion protein, denoted TG-pl-BMP-2, was designed and produced recombinantly. An N-terminal transglutaminase substrate (TG) domain provides covalent attachment to fibrin during coagulation under the influence of the blood transglutaminase factor XIIIa. A central plasmin substrate (pl) domain provides a cleavage site for local release of the attached growth factor from the fibrin matrix under the influence of cell-activated plasmin. A C-terminal human BMP-2 domain provides osteogenic activity. TG-pl-BMP-2 in fibrin was evaluated in vivo in critical-size craniotomy defects in rats, where it induced 76% more defect healing with bone at 3 weeks with a dose of 1 mug/defect than wildtype BMP-2 in fibrin. After a dosing study in rabbits, the engineered growth factor in fibrin was evaluated in a prospective clinical study for pancarpal fusion in dogs, where it induced statistically faster and more extensive bone bridging than equivalent treatment with cancellous bone autograft. The strong healing response shown by fibrin including a bound BMP-2 variant suggests that with the combination of bound growth factor and ingrowth matrix, it may be possible to improve upon the natural growth factor and even upon tissue autograft.
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PMID:Bone repair with a form of BMP-2 engineered for incorporation into fibrin cell ingrowth matrices. 1561 23

Factor XIII (FXIII) is a zymogen that is converted into an active transglutaminase (FXIIIa) by the concerted action of thrombin and Ca2+. Its main task is to crosslink alpha-, and gamma-chains of fibrin and alpha2-plasmin inhibitor to fibrin. By this way FXIIIa strengthens fibrin and protects it from the prompt elimination by fibrinolytic system.The changes of FXIII level in thrombotic diseases are hardly explored and there are contradictory results concerning the protective effect of Val34Leu polymorphism against arterial or venous thrombosis. The results suggest that the thrombo-protective effect of Leu34 allele prevails only in certain genetic and/or environmental constellations.
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PMID:Fibrin stabilization (factor XIII), fibrin structure and thrombosis. 1569 56

Fibrinogen is a large, complex, fibrous glycoprotein with three pairs of polypeptide chains linked together by 29 disulfide bonds. It is 45 nm in length, with globular domains at each end and in the middle connected by alpha-helical coiled-coil rods. Both strongly and weakly bound calcium ions are important for maintenance of fibrinogen's structure and functions. The fibrinopeptides, which are in the central region, are cleaved by thrombin to convert soluble fibrinogen to insoluble fibrin polymer, via intermolecular interactions of the "knobs" exposed by fibrinopeptide removal with "holes" always exposed at the ends of the molecules. Fibrin monomers polymerize via these specific and tightly controlled binding interactions to make half-staggered oligomers that lengthen into protofibrils. The protofibrils aggregate laterally to make fibers, which then branch to yield a three-dimensional network-the fibrin clot-essential for hemostasis. X-ray crystallographic structures of portions of fibrinogen have provided some details on how these interactions occur. Finally, the transglutaminase, Factor XIIIa, covalently binds specific glutamine residues in one fibrin molecule to lysine residues in another via isopeptide bonds, stabilizing the clot against mechanical, chemical, and proteolytic insults. The gene regulation of fibrinogen synthesis and its assembly into multichain complexes proceed via a series of well-defined steps. Alternate splicing of two of the chains yields common variant molecular isoforms. The mechanical properties of clots, which can be quite variable, are essential to fibrin's functions in hemostasis and wound healing. The fibrinolytic system, with the zymogen plasminogen binding to fibrin together with tissue-type plasminogen activator to promote activation to the active enzyme plasmin, results in digestion of fibrin at specific lysine residues. Fibrin(ogen) also specifically binds a variety of other proteins, including fibronectin, albumin, thrombospondin, von Willebrand factor, fibulin, fibroblast growth factor-2, vascular endothelial growth factor, and interleukin-1. Studies of naturally occurring dysfibrinogenemias and variant molecules have increased our understanding of fibrinogen's functions. Fibrinogen binds to activated alphaIIbbeta3 integrin on the platelet surface, forming bridges responsible for platelet aggregation in hemostasis, and also has important adhesive and inflammatory functions through specific interactions with other cells. Fibrinogen-like domains originated early in evolution, and it is likely that their specific and tightly controlled intermolecular interactions are involved in other aspects of cellular function and developmental biology.
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PMID:Fibrinogen and fibrin. 1583 18

The D-dimer antigen is a unique marker of fibrin degradation that is formed by the sequential action of 3 enzymes: thrombin, factor XIIIa, and plasmin. First, thrombin cleaves fibrinogen producing fibrin monomers, which polymerize and serve as a template for factor XIIIa and plasmin formation. Second, thrombin activates plasma factor XIII bound to fibrin polymers to produce the active transglutaminase, factor XIIIa. Factor XIIIa catalyzes the formation of covalent bonds between D-domains in the polymerized fibrin. Finally, plasmin degrades the crosslinked fibrin to release fibrin degradation products and expose the D-dimer antigen. D-dimer antigen can exist on fibrin degradation products derived from soluble fibrin before its incorporation into a fibrin gel, or after the fibrin clot has been degraded by plasmin. The clinical utility of D-dimer measurement has been established in some scenarios, most notably for the exclusion of VTE. This article consists of 2 sections: in the first, the dynamics of D-dimer antigen formation is discussed and an overview of commercially available D-dimer assays is provided. The second section reviews available evidence for the clinical utilization of D-dimer antigen measurement in VTE, as well as emerging areas of D-dimer utilization as a marker of coagulation activation in other clinical settings.
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PMID:D-dimer antigen: current concepts and future prospects. 1900 57

Regenerative medicine requires innovative therapeutic designs to accommodate high morphogen concentrations in local depots, provide their sustained presence, and enhance cellular invasion and directed differentiation. Here we present an example for inducing local bone regeneration with a matrix-bound engineered active fragment of human parathyroid hormone (PTH(1-34)), linked to a transglutaminase substrate for binding to fibrin as a delivery and cell-invasion matrix with an intervening plasmin-sensitive link (TGplPTH(1-34)). The precursor form displays very little activity and signaling to osteoblasts, whereas the plasmin cleavage product, as it would be induced under the enzymatic influence of cells remodeling the matrix, was highly active. In vivo animal bone-defect experiments showed dose-dependent bone formation using the PTH-fibrin matrix, with evidence of both osteoconductive and osteoinductive bone-healing mechanisms. Results showed that this PTH-derivatized matrix may have potential utility in humans as a replacement for bone grafts or to repair bone defects.
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PMID:Bone healing induced by local delivery of an engineered parathyroid hormone prodrug. 1912 52

Factor XIII (FXIII) is a tetrameric zymogen (FXIII-A (2)B (2)) that is converted into an active transglutaminase (FXIIIa) by thrombin and Ca (2+) in the terminal phase of the clotting cascade. By cross-linking fibrin chains and alpha (2) plasmin inhibitor to fibrin, FXIIIa mechanically stabilizes fibrin and protects it from fibrinolysis. Severe deficiency of the potentially active A subunit (FXIII-A) is a rare but severe hemorrhagic diathesis. Delayed umbilical stump bleeding is characteristic, and subcutaneous, intramuscular, and intracranial bleeding occurs with a relatively high frequency in nonsupplemented patients. In addition, impaired wound healing and spontaneous abortion in women are also features of FXIII deficiency. The extremely rare B subunit deficiency results in milder bleeding symptoms. FXIII concentrate is now available for on-demand treatment and primary prophylaxis. A quantitative FXIII activity assay is recommended as a screening test for the diagnosis of FXIII deficiency. For classification purposes, FXIII-A (2)B (2) antigen in the plasma is first determined, and if decreased, further measurement of the individual subunits is recommended in the plasma and FXIII-A in platelet lysate. Analytical aspects of FXIII activity and antigen assays are discussed in this article. There are no hot-spot mutations in the F13A1 and F13B genes, and the majority of causative mutations are missense/nonsense point mutations.
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PMID:Factor XIII Deficiency. 1959 71

Factor XIII (FXIII) is a plasma transglutaminase that cross-links fibrin monomers, alpha(2)-plasmin inhibitor, and so forth. Congenital FXIII deficiency causes lifelong bleeding symptoms. To understand the molecular pathology of FXIII deficiency in vivo, its knockout mice have been functionally analyzed. Because prolonged bleeding times, a sign of defective/abnormal primary hemostasis, were commonly observed in 2 separate lines of FXIII A subunit (FXIII-A) knockout mice, a possible role or roles of FXIII in platelet-related function was investigated in the present study. Although platelet aggregation induced by adenosine diphosphate or collagen was normal, clot retraction (CR) was lost in the platelet-rich plasma (PRP) of FXIII-A knockout mice. In contrast, there was no CR impairment in the PRP of tissue transglutaminase-knockout mice compared with that of wild-type mice. Furthermore, a transglutaminase inhibitor, cystamine, halted CR in the PRP of wild-type mice. These results indicate that the enzymatic activity of FXIII is necessary for CR, at least in mice.
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PMID:Impaired clot retraction in factor XIII A subunit-deficient mice. 1999 13


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