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)

Thromboembolic complications are often seen in patients with nephrotic syndrome. Markers of endothelial cell injury [thrombomodulin, intracellular adhesion molecule, vascular cell adhesion molecule, thrombin activatable fibrinolysis inhibitor (TAFI), protein Z, vascular endothelial growth factor, markers of thrombin and plasmin generation] were studied in 22 patients with nephrotic syndrome. All these parameters studied, except protein Z and D-dimers, were significantly higher in patients with nephrotic syndrome, whereas protein Z was significantly lower when compared with the healthy volunteers. None of the endothelial cell markers (thrombomodulin, P-selectin, E-selectin, intracellular adhesion molecule, vascular cell adhesion molecule), thrombin and plasmin generation markers (thrombin-antithrombin complexes, prothrombin fragments 1 + 2, plasmin-antiplasmin complexes, D-dimers), protein C, protein Z, vascular endothelial growth factor, and TAFI concentration and activity were directly correlated with the level of proteinuria, albumin, cholesterol, triglycerides or creatinine, except significant positive correlations between TAFI activity and serum creatinine, E-selectin and albumin as well as negative correlations between plasmin-antiplasmin complexes and proteinuria. In these patients, there is evidence of endothelial cell injury and probably secondary activation of the coagulation cascade. Elevated circulating TAFI antigen and activity might be a new link in the pathogenesis of impaired fibrinolysis and the progression of atherosclerosis in nephrotic syndrome. Protein Z deficiency might also contribute to the enhanced risk of thromboembolic complications in nephrotic syndrome.
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PMID:Markers of endothelial cell injury and thrombin activatable fibrinolysis inhibitor in nephrotic syndrome. 1243 47

Amifostine (WR-2721) is an inorganic thiophosphate-cytoprotective agent developed to selectively protect normal tissues against the toxicity of chemotherapy and radiation. We have previously shown that amifostine protects both chicken embryo chorioallantoic membrane (CAM) vessels and cells from the effects of X-rays. In the present work, we studied the effect of amifostine on angiogenesis in vivo, using the CAM model. Amifostine decreased the number of CAM vessels in a dose-dependent manner, without being toxic for the tissue. It also decreased the mRNA levels of both vascular endothelial growth factor (VEGF) isoforms VEGF(165) and VEGF(190), 6 and up to 48 h after its application onto the CAM. Similarly, it decreased the mRNA levels of inducible nitric-oxide synthase, 24 and 48 h after drug application. Furthermore, amifostine decreased the deposited amounts of laminin and collagen I 24 h after its application, without affecting the expression of the corresponding genes. The protein amounts and activity of matrix metalloproteinase-2 were not affected, whereas the expression of the corresponding gene was decreased up to 48 h after drug application. Finally, the activity of plasmin was increased 6 h after amifostine application and remained increased at later time points. These findings suggest that amifostine alters the expression of several molecules implicated in the angiogenesis process and affects the composition of the extracellular matrix in a way that leads to inhibition of angiogenesis. Such an antiangiogenic action of amifostine, together with its radioprotective effects, further supports its use in combination with radiotherapy for increased therapeutic efficacy.
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PMID:Amifostine inhibits angiogenesis in vivo. 1253 28

Angiogenesis and lymphangiogenesis are regulated by members of the vascular endothelial growth factor (VEGF) family of cytokines, which mediate their effects via tyrosine kinase VEGF receptors -1, -2, and -3. We have used wild-type and mutant forms of VEGFs -A, -B, and -C, a pan-VEGFR tyrosine kinase inhibitor (SU5416) as well as neutralizing anti-VEGFR-2 antibodies, to determine which VEGF receptor(s) are required for bovine endothelial cell invasion and tube formation in vitro. This was compared to the ability of these cytokines to induce expression of members of the plasminogen activator (PA)-plasmin system. We found that cytokines which bind VEGFR-2 (human VEGF-A, human VFM23A, human VEGF-C(deltaNdeltaC), and rat VEGF-C(152)) induced invasion, tube formation, urokinase-type-PA, tissue-type-PA, and PA inhibitor-1, invasion and tube formation as well as signaling via the MAP kinase pathway were efficiently blocked by SU5416 and anti-VEGFR-2 antibodies. In contrast, cytokines and mutants which exclusively bind VEGFR-1 (human VFM17 and human VEGF-B) had no effect on invasion and tube formation or on the regulation of gene expression. We were unable to identify cytokines which selectively stimulate bovine VEGFR-3 in our system. Taken together, these findings point to the central role of VEGFR-2 in the angiogenic signaling pathways induced by VEGF-C(deltaNdeltaC) and VEGF-A.
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PMID:Vascular endothelial growth factor (VEGF) receptor-2 signaling mediates VEGF-C(deltaNdeltaC)- and VEGF-A-induced angiogenesis in vitro. 1270 23

Tissue-type plasminogen activator (tPA) is a multidomain serine protease that converts the zymogen plasminogen to plasmin. tPA contains two kringle domains which display considerable sequence identity with those of angiostatin, an angiogenesis inhibitor. TK1-2, a recombinant kringle domain composed of t-PA kringles 1 and 2 (Ala(90)-Thr(263)), was produced by both bacterial and yeast expression systems. In vitro, TK1-2 inhibited endothelial cell proliferation stimulated by basic fibroblast growth factor, vascular endothelial growth factor, and epidermal growth factor. It did not inhibit proliferation of non-endothelial cells. TK1-2 also inhibited in vivo angiogenesis in the chick embryo chorioallantoic membrane model. These results suggest that the recombinant kringle domain of t-PA is a selective inhibitor of endothelial cell growth and identifies this molecule as a novel anti-angiogenic agent.
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PMID:Inhibition of endothelial cell proliferation by the recombinant kringle domain of tissue-type plasminogen activator. 1272 18

Flavonoids have been proposed to act as chemopreventive agents in numerous epidemiological studies and have been shown to inhibit angiogenesis and proliferation of tumor cells and endothelial cells in vitro. Angiogenesis requires tightly controlled extracellular matrix degradation mediated by extracellular proteolytic enzymes including matrix metalloproteinases (MMPs) and serine proteases, in particular, the urokinase-type plasminogen activator (uPA)-plasmin system. In this study, we have investigated the antiangiogenic mechanism of the flavonoids, genistein, apigenin, and 3-hydroxyflavone in a human umbilical vein endothelial cell (HUVEC) model. The stimulation of serum-starved HUVECs with vascular endothelial growth factor/basic fibroblast growth factor (VEGF/bFGF) caused marked increase in MMP-1 production and induced the pro-MMP-2 activation accompanied by the increase in MT1-MMP expression. However, pretreatment with flavonoids before VEGF/bFGF stimulation completely abolished the VEGF/bFGF-stimulated increase in MMP-1 and MT1-MMP expression and pro-MMP-2 activation. Genistein blocked VEGF/bFGF-stimulated increase in TIMP-1 expression and decrease in TIMP-2 expression. Apigenin and 3-hydroxyflavone further decreased TIMP-1 expression below basal level and completely abolished TIMP-2 expression. VEGF and bFGF stimulation also significantly induced uPA expression, most strikingly the level of 33 kDa uPA, and increased the expression of PA inhibitor (PAI)-1. Genistein, apigenin, and 3-hydroxyflavone effectively blocked the generation of 33 kDa uPA, and further decreased the activity of the 55 kDa uPA and the expression of PAI-1 below the basal level. In conclusion, these data suggest that genistein, apigenin, and 3-hydroxyflavone inhibit in vitro angiogenesis, in part via preventing VEGF/bFGF-induced MMP-1 and uPA expression and the activation of pro-MMP-2, and via modulating their inhibitors, TIMP-1 and -2, and PAI-1.
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PMID:Flavonoids inhibit VEGF/bFGF-induced angiogenesis in vitro by inhibiting the matrix-degrading proteases. 1276 86

We here report that the arterial blood flow after endothelial injury in mice deficient in alpha 2-antiplasmin (alpha 2-AP-/- mice) was well maintained compared with that of wild-type mice. Moreover, the development of neointima 4 weeks after injury in alpha 2-AP-/- mice was significantly decreased. Histologic observations showed a prompt recovery of endothelial cells with a much higher proliferating index in repaired endothelium in alpha 2-AP-/- mice. The amount of secreted vascular endothelial growth factor (VEGF) by explanted vascular smooth muscle cells (SMCs) from alpha 2-AP-/- mice was significantly increased. In separate experiments using a human endothelial cell (EC) line, we could demonstrate that plasminogen binds to ECs and that this binding can be prevented by alpha 2-AP. Finally, an injection of either an anti-VEGF receptor-1 antibody or alpha 2-AP reduced the prompt endothelial healing. alpha 2-AP is the main inactivator of plasmin, which cleaves extracellular matrix-bound VEGF to release a diffusible proteolytic fragment. Lack of alpha 2-AP, therefore, could lead to a local over-release of VEGF by the continuously active plasmin in the injured area, which could result in a prompt re-endothelialization after vascular injury. Our results provide new insight into the role of alpha 2-AP and VEGF in the pathogenesis of re-endothelialization following vascular injury.
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PMID:Lack of alpha 2-antiplasmin promotes re-endothelialization via over-release of VEGF after vascular injury in mice. 1289 71

Fibrin is a temporary matrix which not only covers a wound, but also provides a structure for invading cells during healing. Changes in the polymerization conditions before gelation of the clot affect the structure of fibrin and thus might influence the interaction with invading cells. Therefore we tested whether changes in the fibrin structure influence the formation of capillary-like tubular structures by human microvascular endothelial cells (hMVEC) in an in vitro angiogenesis model. Opaque [125I]fibrin structures prepared at pH 7.0, fibrin matrices at pH 7.4 and transparent [125I]fibrin structures prepared at pH 7.8 were neutralized (pH 7.4) before seeding hMVEC on top of them in confluent density. Endothelial cells were stimulated with a growth factor [basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF)165] and a cytokine [tumor necrosis factor (TNF)-alpha] to induce the u-PA/u-PA receptor-dependent formation of capillary-like tubular structures. The formation of these structures was quantified by determining the length of the invasive structures by image analysis and by measuring the accompanying [125I]fibrin degradation. Ingrowth of tubular structures proceeded at a faster rate in opaque matrices consisting of thick fibrin fibers as compared to transparent gels with fine fibrin fibers. The more rapid ingrowth of tubular structures in opaque fibrin gels induced by bFGF/TNF-alpha or VEGF165/TNF-alpha was accompanied by a larger extent of fibrin degradation. Both processes were inhibited by aprotinin and epsilon-aminocaproic acid indicating the involvement of plasmin. They were also inhibited by anti-u-PA or anti-u-PA receptor IgG, but not by anti-t-PA IgG, suggesting the involvement of cell-bound u-PA activity. However, in the opaque fibrin gels, the tubular structures dissolved upon prolonged incubation due to excessive fibrin degradation. Simulation of hMVEC with bFGF alone did not induce tubular structures, but ca used a high degree of t-PA- and plasmin-dependent fibrin lysis, and, after several days, a partial detachment of sheets of cells. Gradual inhibition of the excessive fibrin degradation by a series of aprotinin concentrations did not lead to tube formation in bFGF-treated cells. These data indicate that the formation and stability of tubular structures by hMVEC in fibrin is accompanied by controlled fibrinolysis and depends critically not only on cell-bound u-PA-dependent plasminogen activation, but also on the fibrin structure. Because the fibrin structure is largely influenced by the conditions in which fibrin has been polymerized, these conditions may have considerable impact on angiogenesis during wound healing and vascularization of tumour stroma.
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PMID:Influence of fibrin structure on the formation and maintenance of capillary-like tubules by human microvascular endothelial cells. 1451 71

Human tissue factor pathway inhibitor-2 (TFPI-2) is a matrix-associated Kunitz inhibitor that inhibits the plasmin- and trypsin-mediated activation of zymogen matrix metalloproteinases involved in tumor progression, invasion, and metastasis. To directly assess its role in tumor growth and metastasis in vivo, we stably transfected HT-1080 fibrosarcoma cells expressing either fully active wild-type human TFPI-2 (WT) or inactive R24Q TFPI-2 (QT) and examined their ability to form tumors and metastasize in athymic mice in comparison to mock-transfected cells (MT). MT and QT fibrosarcoma tumors grew 2 to 3 times larger than WT tumors. Tumor metastasis was confined to the lung and was observed in 75% of mice treated with either MT or QT cells, whereas only 42% of mice treated with WT cells developed lung metastases. Real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analyses of each tumor group revealed 3- to 6-fold lower levels of murine vascular endothelial growth factor gene expression in WT tumors in relation to either MT or QT tumors. Comparative tumor gene expression analysis revealed that several human genes implicated in oncogenesis, invasion, metastasis, apoptosis, and angiogenesis had significantly altered levels of expression in WT tumors. Our collective data demonstrate that secretion of inhibitory TFPI-2 by a highly metastatic tumor cell markedly inhibits its growth and metastasis in vivo by regulating pericellular extracellular matrix (ECM) remodeling and angiogenesis.
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PMID:The effect of human tissue factor pathway inhibitor-2 on the growth and metastasis of fibrosarcoma tumors in athymic mice. 1452 59

We investigated the effect of highly purified eicosapentaenoic acid ethyl ester (EPA-E) on blood coagulation abnormalities and dysfunction of vascular endothelial cells in spontaneously diabetic Otsuka Long-Evans Tokushima Fatty rats. The animals were treated with either EPA-E or lard at a daily dose of 0.3 g/kg/day for 52 weeks by gavage, and their coagulation/fibrinolytic parameters, platelet aggregation, and functions of the vascular endothelial cells were examined. EPA-E significantly improved coagulation-related parameters including prothrombin time, activated partial thromboplastin time, fibrinogen level, and activities of factor II, V, VII, VIII, IX, X, XI, and XII, and antithrombin III, and fibrinolysis-related parameters including plasminogen, tissue-type plasminogen activator, alpha(2)-plasmin inhibitor, and plasminogen activator inhibitor. It also suppressed ADP- or collagen-induced platelet aggregation and the cholesterol/phospholipid molar ratio in platelet membranes at a dose of 0.3 g/kg. In addition, it significantly increased the migration activity of vascular endothelial cells, and decreased the binding of vascular endothelial cells to vascular endothelial growth factor. In contrast, lard had no effect on hypercoagulation, hypofibrinolysis, and platelet hyperaggregation but significantly aggravated the dysfunction of vascular endothelial cells. These data demonstrate that EPA-E beneficially altered certain factors known to promote thrombosis and atherosclerosis in this animal model.
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PMID:Long-term administration of highly purified eicosapentaenoic acid ethyl ester improves blood coagulation abnormalities and dysfunction of vascular endothelial cells in Otsuka Long-Evans Tokushima fatty rats. 1461 17

Intervertebral disc herniation (HD) is one of the most common orthopaedic conditions. MRI analysis of HD has revealed a spontaneous resorption mechanism related with neo-vascularization. It appears that the interaction of activated macrophages with disc tissues leads to the generation of inflammatory cytokines. Moreover, inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) is required for the induction of angiogenesis inducing factors such as vascular endothelial growth factor (VEGF) or matrix degrading enzymes such as MMP-3, MMP-7 and plasmin. We hypothesized that these molecules play a crucial role during spontaneous HD resorption. In this study, we have examined the sequential expression of these molecules using a co-culture system which is composed of the interaction of activated macrophages and disc tissues as a model of the acute response of inflammation occurred in HD. We have also considered the mechanism of activating latent MMPs during HD resorption process. Current our results indicate that upregulation of both TNF-alpha mRNA and protein expressions occur first in the inflammation induced by HD. VEGF upregulation follows the increased level of TNF-alpha expression. Both plasmin and MMP-3 are upregulated at later time points. We also demonstrate that both TNF-alpha and VEGF induce upregulated expression of urokinase-type plasminogen activator (u-PA). Our previous work has demonstrated that TNF-alpha could upregulate the expression of VEGF, MMP-3 and MMP-7 in the co-culture system. It has been reported that plasmin could affect to activate latent MMPs. Based on these findings, we suggest that TNF-alpha acts as the initiator of inflammation following contact between macrophages and disc chondrocytes and that plasmin and u-PA play a crucial role in activation of MMPs. We propose a spontaneous HD resorption cascade. Further understanding of the resorption process may provide future novel therapies for HD.
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PMID:Sequential dynamics of inflammatory cytokine, angiogenesis inducing factor and matrix degrading enzymes during spontaneous resorption of the herniated disc. 1518 52


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