Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasminogen activator inhibitor-1 (PAI-1) inhibits the tissue plasminogen activator (tPA) and urokinase activation of plasminogen to plasmin, a protease of trypsin-like specificity which is involved in a number of processes, including fibrinolysis, matrix degradation and angiogenesis. Both phorbol esters and cAMP elevating compounds have been shown to modulate PAI-1 and tPA expression in endothelial cell culture. HBGF-1 (previously designated endothelial cell growth factor) stimulates endothelial cell growth in vitro and is angiogenic in vivo. We have reported that removal of HBGF-1 from human umbilical vein endothelial cell (HUVEC) media results in an approximately 5-fold increase in PAI-1 mRNA levels and in PAI-1 protein secreted into the media by 20 h. Here we report the effects of HBGF-1 on the phorbol ester and cAMP modulation of HUVEC PAI-1 expression. The phorbol ester PMA induced an approximate 5-fold increase in PAI-1 mRNA levels at 4 h, which returned to base line by 20 h, with or without HBGF-1 present in the media. This increase in PAI-1 mRNA levels was mediated by an increase in PAI-1 gene transcription and was abated in the presence of cycloheximide. Treatment of cells with the adenylate cyclase activator forskolin or the phosphodiesterase inhibitor HL 725, in the presence of HBGF-1 or immediately after its withdrawal, decreased PAI-1 mRNA levels and protein secreted into the conditioned media by 20 h. However, forskolin or HL 725 addition had little or no effect on PAI-1 mRNA when added 20 h after HBGF-1 withdrawal. Both the PMA and HBGF-1 modulation of PAI-1 were abolished by treatment with the protein kinase inhibitor H-7. Treatment of HUVEC with HBGF-1 had no acute effect on intracellular inositol phosphate hydrolysis or cAMP levels. Further studies on intracellular pathways involved in HBGF-1 modulation of PAI-1 will enhance our understanding of the role these factors play in cellular proliferation and angiogenesis.
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PMID:Heparin-binding growth factor-1 modulation of plasminogen activator inhibitor-1 expression. Interaction with cAMP and protein kinase C-mediated pathways. 170 36

This study was designed to determine the relative activity of basic fibroblast growth factor (bFGF), vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), platelet-derived growth factor (PDGF), platelet-derived endothelial cell growth factor (PD-ECGF), hepatocyte growth factor (HGF), and interleukin-8 (IL-8) in regulating endothelial cell division, migration, degradation of the extracellular matrix (ECM), morphogenesis, and survival. Human umbilical vein endothelial cells (HUVEC) were treated with different concentrations of the six cytokines. bFGF was the most potent mitogen followed by VEGF/VPF and PD-ECGF. VEGF/VPF and bFGF also enhanced the survival of the endothelial cells in serum-free medium. Interstitial collagenase (MMP-1) and urokinase plasminogen activator (uPA) were significantly upregulated only by bFGF. HGF, bFGF, and VEGF/VPF induced chemotactic migration of the endothelial cells, but only HGF (scatter factor) enhanced nondirectional motility. The organization of endothelial cells to form tubes on Matrigel was induced by bFGF and, to a lesser extent, by VEGF/VPF and IL-8. Permeability across endothelial cell monolayers was induced only by VEGF/VPF. These data demonstrate that different angiogenic molecules differentially regulate distinct steps in the process of angiogenesis, suggesting that any given molecule may be necessary but in itself insufficient for establishment of a viable vasculature.
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PMID:Regulation of distinct steps of angiogenesis by different angiogenic molecules. 949 33

Chromogenic assays, immunoblotting, and Northern blot hybridization methods were employed to assess the effects of various agonists on the production of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) by the lymphatic endothelium (LEC). Fibrin autography showed that plasminogen-dependent fibrinolytic activity occurred at M(r) of 110 kDa, which represents a complex of tPA with PAI-1, and 65- and 55-kDa bands corresponding to tPA and uPA, respectively. The fractionation of lymph collected from ovine lymphatic vessels also produced a prominent lytic band of approximately 110 kDa, suggesting the formation of PA/PAI complexes in lymph. The stimulation of various agonists produced large-scale increases in tPA mRNA, as shown by Northern blot hybridization analyses. The effects of ECGF, histamine, and LPS on the presence of tPA and on enhancing the levels of mRNA reached maximum activity at 4 h and declined to levels below that of controls by 8 h. However, phorbol-treated cells exhibited reduced levels of tPA mRNA at 4 h, but was significantly increased by 8 h. A large-scale increase in PAI-1 mRNA steady-state levels was also stimulated by the agonists used in these studies. Both the 3.4- and 2.4-kb species of PAI-1 mRNA were increased. These observations demonstrated that tPA and PAI-1 are produced and secreted by LEC monolayer cultures and are also present in lymph.
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PMID:Stimulation of plasminogen activator and inhibitor in the lymphatic endothelium. 1107 36