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 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

Crescentic glomerulonephritis is characterized by glomerular fibrin deposition, and experimental crescentic glomerulonephritis has been shown to be fibrin-dependent. Net fibrin deposition is a balance between activation of the coagulation system causing glomerular fibrin deposition and fibrin removal by the plasminogen-plasmin (fibrinolytic) system. Plasminogen activator inhibitor-1 (PAI-1) inhibits fibrinolysis by inhibiting plasminogen activators and has effects on leukocyte recruitment and matrix deposition. To test the hypothesis that the presence of PAI-1 and its levels were a determinant of injury in crescentic glomerulonephritis, accelerated anti-glomerular basement membrane glomerulonephritis was induced in mice genetically deficient in PAI-1 (PAI-1 -/-), PAI-1 heterozygotes (PAI-1 +/-), and mice engineered to overexpress PAI-1 (PAI-1 tg). Compared with strain-matched genetically normal animals, PAI-1 -/- mice with glomerulonephritis developed fewer glomerular crescents, less glomerular fibrin deposition, fewer infiltrating leukocytes, and less renal collagen accumulation at day 14 of disease. The reduction in disease persisted at day 28, when injury had become more established. In contrast, mice overexpressing the PAI-1 gene (PAI-1 tg), that have basal plasma and renal PAI-1 levels several times, normal developed increased glomerular crescent formation, more glomerular fibrin deposition, increased numbers of infiltrating leukocytes, and more renal collagen at both time points. These studies demonstrate that PAI-1 is a determinant of glomerular fibrin deposition and renal injury in crescentic glomerulonephritis.
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PMID:Plasminogen activator inhibitor-1 is a significant determinant of renal injury in experimental crescentic glomerulonephritis. 1276 Dec 49

Hepatocyte growth factor activator inhibitor-1 (HAI-1) is an integral membrane protein expressed on epithelial cells and contains two extracellular Kunitz domains (N-terminal KD1 and C-terminal KD2) known to inhibit trypsin-like serine proteases. In tumorigenesis and tissue regeneration, HAI-1 regulates the hepatocyte growth factor (HGF)/c-Met pathway by inhibiting the activity of HGF activator (HGFA) and matriptase, two serine proteases that convert pro-HGF into its biologically active form. By screening a placental cDNA library, we discovered a new splice variant of HAI-1 designated HAI-1B that contains an extra 16 amino acids adjacent to the C terminus of KD1. To investigate possible consequences on Kunitz domain function, a soluble form of HAI-1B (sHAI-1B) comprising the entire extracellular domain was produced. First, we found that sHAI-1B displayed remarkable enzyme specificity by potently inhibiting only HGFA (IC50 = 30.5 nm), matriptase (IC50 = 16.5 nm), and trypsin (IC50 = 2.4 nm) among 16 serine proteases examined, including plasminogen activators (urokinase- and tissue-type plasminogen activators), coagulation enzymes thrombin, factors VIIa, Xa, XIa, and XIIa, and activated protein C. Relatively weak inhibition was found for plasmin (IC50 = 399 nm) and plasma kallikrein (IC50 = 686 nm). Second, the functions of the KD1 and KD2 domains in sHAI-1B were investigated using P1 residue-directed mutagenesis to show that inhibition of HGFA, matriptase, trypsin, and plasmin was due to KD1 and not KD2. Furthermore, analysis by reverse transcription-PCR demonstrated that HAI-1B and HAI-1 were co-expressed in normal tissues and various epithelial-derived cancer cell lines. Both isoforms were up-regulated in eight examined ovarian carcinoma specimens, three of which had higher levels of HAI-1B RNA than of HAI-1 RNA. Therefore, previously demonstrated roles of HAI-1 in various physiological and pathological processes likely involve both HAI-1B and HAI-1.
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PMID:Tissue expression, protease specificity, and Kunitz domain functions of hepatocyte growth factor activator inhibitor-1B (HAI-1B), a new splice variant of HAI-1. 1281 39

During recent years it has become increasingly recognized that the plasmin activation system is involved in the development of atherosclerosis. In this paper, we have studied the contribution of the plasminogen activation system in the development of atherosclerosis by cross-breeding apoE3-Leiden mice, which have a human-like lipid profile, with mice deficient in PAI-1 (plasminogen-activator inhibitor-1), u-PA (urokinase plasminogen activator), and t-PA (tissue plasminogen activator). Genetic compound offspring was used to evaluate the progression of atherosclerotic lesions after they were fed a variant atherogenic diet for 12 weeks. Lesion area of plaques in the aortic valve was not significantly different in apoE3-Leiden:PAI -/- and apoE3-Leiden:u-PA -/- mice as compared to apoE3-Leiden mice. In contrast, a significant 70% reduction of the lesion area was observed in apoE3-Leiden:t-PA -/- mice as compared to control group apoE3-Leiden mice. In addition the early, regular fatty streaks and mild plaques increased in apoE3-Leiden:t-PA -/- mice, whereas the severe plaques (type IV and V) decreased in these animals. A lower deposition of collagen was observed in the atherosclerotic lesions of apoE3-Leiden:t-PA -/- mice as compared with apoE3-Leiden mice. Our results indicate for the first time that t-PA deficiency delayed the atherosclerotic process in this mouse model.
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PMID:Genetic deletion of tissue-type plasminogen activator (t-PA) in APOE3-Leiden mice reduces progression of cholesterol-induced atherosclerosis. 1451 93

Intravascular fibrin deposition is believed to play an important role in the development of intimal hyperplasia, which is a hallmark of several human vascular disorders, including atherosclerosis and restenosis after balloon angioplasty. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor or tissue- and urinary-type plasminogen activator, plays a key role in fibrin homeostasis by controlling plasmin formation. PAI-1 may also modulate vascular pathology via alternative pathways, such as inhibiting activated protein C and altering interactions between vascular smooth muscle cells and the extracellular matrix. The diverse functional profile of PAI-1 likely accounts for the variation observed in its impact on intimal hyperplasia in different disease models. This review examines recent studies addressing the vascular function of PAI-1, and those assessing the role of fibrin as a downstream mediator of PAI-1's effects.
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PMID:Plasminogen activator inhibitor 1, fibrin, and the vascular response to injury. 1526 92

Plasminogen activator inhibitor-1 (PAI-1) may contribute to renal fibrosis because of its involvement in matrix (ECM) accumulation through inhibition of plasmin-dependent ECM degradation. The aim of this study is to determine urinary PAI-1 concentrations and its intrarenal localization in patients with various renal diseases and to identify inducers for PAI-1 expression in human cultured proximal renal tubular cells (HRCs). Urinary PAI-1 concentrations were significantly higher in patients with overt diabetic nephropathy (DN, n=36) than in proliferative glomerulonephritis (PGN, n=8), nephrotic syndrome (NS, n=10) and healthy controls (n=12). Urinary PAI-1 concentrations (ng/gCr) were directly correlated with urinary N-acetyl glucosaminidase (NAG) levels (r=0.58, p<0.05). As for intrarenal localization of PAI-1 antigen, strong stainings for PAI-1 were observed in proximal tubular cells of renal biopsy samples from patients with DN, while no stainings for PAI-1 were found in renal tissues of PGN or NS. Immunoblot analysis revealed the presence of PAI-1 protein in whole cell lyzates from HRCs grown to semiconfluency. Exposure of growth-arrested HRCs with hypoxia (1% O2) or TNF-alpha (10 ng/ml) for 24 hours increased the secretion rate of PAI-1 protein by about 2.0-fold, while 24-hour treatment with high glucose (450 mg/dl) did not increase PAI-1 secretion at all, compared with that of the control cells under normal glucose (100 mg/dl) and normoxia (18% O2). These findings suggest that PAI-1 expression is upregulated especially in the proximal renal tubular cells of DN, which may be explained partially by hypoxia and inflammatory cytokines but not high glucose.
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PMID:[Diabetic nephropathy and plasminogen activator inhibitor 1 in urine samples]. 1528 63

Plasminogen activator inhibitor-1 (PAI-1) is an important component of the plasminogen/plasmin system as it is the main inhibitor of tissue-type and urokinase-type plasminogen activator. Consequently, PAI-1 plays an important role in cardiovascular diseases (mainly through inhibition of t-PA) and in cell migration and tumor development (mainly through inhibition of u-PA). As a member of the serpin superfamily, PAI-1 shares important structural properties with other serpins. However, PAI-1 also exhibits unique conformational and functional properties. The current paper provides an overview of the knowledge on PAI-1 gathered since its discovery two decades ago. We are discussing (a) its structural properties and their subsequent association with the functional properties, (b) its role in a wide variety of (patho)physiological processes and (c) a number of strategies to interfere with its functional properties eventually aiming at pharmacological modulation of this risk factor.
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PMID:Plasminogen activator inhibitor-1. 1537 15

Plasminogen activator inhibitor-1 (PAI-1), a 45-kDa serine proteinase inhibitor with reactive site peptide bond Arg345-Met346, is the main physiological plasminogen activator inhibitor. It occurs in human plasma at an antigen concentration of about 20 ng mL(-1). Besides the active inhibitory form of PAI-1 that spontaneously converts to a latent form, also a substrate form exists that is cleaved at the P1-P1' site by its target enzymes, but does not form stable complexes. Besides its role in regulating hemostasis, PAI-1 plays a role in several biological processes dependent on plasminogen activator or plasmin activity. Studies with transgenic mice have revealed a functional role for PAI-1 in wound healing, atherosclerosis, metabolic disturbances such as obesity and insulin resistance, tumor angiogenesis, chronic stress, bone remodeling, asthma, rheumatoid arthritis, fibrosis, glomerulonephritis and sepsis. It is not always clear if these functions depend on the antiproteolytic activity of PAI-1, on its binding to vitronectin or on its intereference with cellular migration or matrix binding.
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PMID:Pleiotropic functions of plasminogen activator inhibitor-1. 1563 64

BACKGROUND: Breast cancer cells frequently metastasize to the skeleton and induce extensive bone destruction. Cancer cells produce proteinases, including matrix metalloproteinases (MMPs) and the plasminogen activator system (PAS) which promote invasion of extracellular matrices, but whether these proteinases degrade bone matrix is unclear. To characterize the role that breast cancer cell proteinases play in bone degradation we compared the effects of three human breast cancer cell lines, MDA-MB-231, ZR-75-1 and MCF-7 with those of a normal breast epithelial cell line, HME. The cell lines were cultured atop radiolabelled matrices of either mineralized or non-mineralized bone or type I collagen, the principal organic constituent of bone. RESULTS: The 3 breast cancer cell lines all produced significant degradation of the 3 collagenous extracellular matrices (ECMs) whilst the normal breast cell line was without effect. Breast cancer cells displayed an absolute requirement for serum to dissolve collagen. Degradation of collagen was abolished in plasminogen-depleted serum and could be restored by the addition of exogenous plasminogen. Localization of plasmin activity to the cell surface was critical for the degradation process as aprotinin, but not alpha2 antiplasmin, prevented collagen dissolution. During ECM degradation breast cancer cell lines expressed urokinase-type plasminogen activator (u-PA) and uPA receptor, and MMPs-1, -3, -9,-13, and -14. The normal breast epithelial cell line expressed low levels of MMPs-1, and -3, uPA and uPA receptor. Inhibitors of both the PAS (aprotinin and PA inhibitor-1) and MMPs (CT1166 and tisue inhibitor of metalloproteinase) blocked collagen degradation, demonstrating the requirement of both plasminogen activation and MMP activity for degradation. The activation of MMP-13 in human breast cancer cells was prevented by plasminogen activator inhibitor-1 but not by tissue inhibitor of metalloproteinase-1, suggesting that plasmin activates MMP-13 directly. CONCLUSIONS: These data demonstrate that breast cancer cells dissolve type I collagen and that there is an absolute requirement for plasminogen activation and MMP activity in the degradation process.
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PMID:Human breast cancer cell-mediated bone collagen degradation requires plasminogen activation and matrix metalloproteinase activity. 1570 Nov 64

Annexin II (ANXII) is a receptor for tissue plasminogen activator and plasminogen for the conversion to plasmin, which, in turn, induces metalloproteinase-9 (MMP-9). 17beta-Estradiol (E(2)) is reported to decrease plasminogen activity inhibitor-1 and increase plasmin and matrix metalloproteinase activity. However, the combined effects of estrogen and statins on macrophage MMP-9 activity and ANXII expression remain unclear. Treatment of J774A.1 macrophages with 1.0-100 nM of E(2) for 24h increased both MMP-9 activity and ANXII expression in a dose-dependent manner (p<0.05). Preincubation with EGTA (10mM) released ANXII from the cell membrane and inhibited the E(2)-mediated MMP-9 activity as did incubation of macrophages with anti-annexin IgG. In the presence or absence of E(2) (5 nM), simvastatin treatment in the range of 0.1-5.0 microM significantly reduced macrophage MMP-9 enzymatic activity (p<0.005) in a dose-dependent manner. In the presence or absence of E(2), simvastatin also decreased ANXII expression (p<0.05). These findings indicate that ANXII plays a central role in modulating the enzymatic activity of MMP-9 in response to E(2) and that E(2)-mediated ANXII expression and MMP-9 activity can be prevented by simvastatin. Prevention of E(2)-mediated activation of MMP-9 by simvastatin suggests that concurrent statin use may account for early event risk of myocardial infarction seen with hormone therapy in recent clinical trials.
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PMID:Role of annexin II in estrogen-induced macrophage matrix metalloproteinase-9 activity: the modulating effect of statins. 1638 57


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