Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When SW620 colon cancer-derived metastatic cells were exposed to nanomolar concentrations of Taxol, colchicine or (Z)-3,5,4'-trimethoxystilbene (R3), huge aneuploid, polynuclear cells survived the treatment. These cells released considerable amounts of the matrix metalloproteinase matrilysin (MMP-7), and tissue-type plasminogen activator (tPA) into the surrounding culture medium. MMP-7, and other proteolytic enzymes were highly expressed by these cells. In spite of their enormous size, the polyploid cells exhibited a considerable migratory capacity, as was demonstrated by their migration through an artificial basement membrane. While colchicine and R3-treated cells showed an inverse relationship between drug concentration and invasiveness, treatment with Taxol increased the capacity of the SW620 cells to penetrate through the membrane. The invasive capacity was not correlated with the induction and release of proteolytic enzymes. The idea that expression and release of proteolytic enzymes is a fundamental prerequisite of tumour cell invasiveness is generally accepted. The ability of the cells to respond to chemotactic signalling, and the filamentous structures of the cells, together with several cell adhesion factors, which are the basis of cell migration, are prerequisites of invasiveness. These factors are presumably different in the aneuploid cells produced by Taxol, colchicine and R3, and await scrutiny.
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PMID:Polyploidisation of metastatic colon carcinoma cells by microtubule and tubulin interacting drugs: effect on proteolytic activity and invasiveness. 1537 54

Reperfusion therapy with tissue plasminogen activator (tPA) is a rational therapy for acute ischemic stroke. Properly titrated use of tPA improves clinical outcomes. However, there is also an associated risk of hemorrhagic transformation after tPA therapy. Emerging data now suggest that some of these potentially neurotoxic side effects of tPA may be due to its signaling actions in the neurovascular unit. Besides its intended role in clot lysis, tPA is also an extracellular protease and signaling molecule in brain. tPA mediates matrix remodeling during brain development and plasticity. By interacting with the NMDA-type glutamate receptor, tPA may amplify potentially excitotoxic calcium currents. At selected concentrations, tPA may be vasoactive. Finally, by augmenting matrix metalloproteinase (MMP) dysregulation after stroke, tPA may degrade extracellular matrix integrity and increase risks of neurovascular cell death, blood-brain barrier leakage, edema, and hemorrhage. Understanding these pleiotropic actions of tPA may reveal new therapeutic opportunities for combination stroke therapy.
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PMID:Mechanisms of hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke. 1545 42

The spontaneously hypertensive stroke-prone rat (SHR-SP) is an experimental model of malignant hypertension which lead to secondary alterations of the extracellular matrix. Our aim was to determine ACE-inhibitor related changes of proteases involved in the reconstruction of the extracellular matrix in the brain. Twelve SHR-SP rats were randomized into two groups. Each group was treated with either an antihypertensive dose of ramipril or placebo for 6 months. Brain tissue plasminogen activator (t-PA) and urokinase (u-PA) were quantified by using casein-dependent plasminogen zymography, matrix metalloproteinase (MMP)-2 and MMP-9, by MMP-zymography, and tissue inhibitor of MMP (TIMP)-1 and -2, by reverse zymography. The amounts of u-PA, t-PA, and MMPs were significantly reduced in animals treated with ACE inhibitor. Plasminogen zymography showed a 39% reduction of u-PA in the basal ganglia (p < 0.0001); t-PA expression was reduced by 26% in the cortex and by 33% in the basal ganglia (p < 0.0001). MMP-2 expression was reduced by 15% in the cortex (p < 0.05) and by 10% in the basal ganglia (p < 0.05); MMP-9 expression significantly decreased by 37% in the cortex and by 25% in the basal ganglia (p < 0.0001 each). No differences were observed in the amount of TIMP-1 or TIMP-2. These findings provide new insights into the biochemical mechanisms underlying extracellular matrix proliferation and its modulation by ACE inhibitors. Therapeutic alterations that influence the proteolytic systems might prove important in the prevention of extracellular matrix accumulation and secondary microvascular vessel wall changes.
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PMID:ACE inhibition reduces activity of the plasminogen/plasmin and MMP systems in the brain of spontaneous hypertensive stroke-prone rats. 1572 Dec 22

Glutamate is accumulated in abundance during the early period of experimental hematoma, and the activation of N-methyl-D-aspartate (NMDA) receptors by glutamate can result in an influx of calcium and neuronal death in cases of intracerebral hemorrhage (ICH). Memantine, which is known to be a moderate-affinity, uncompetitive, NMDA receptor antagonist, was investigated with regard to its ability to block the glutamate overstimulation and tissue plasminogen activator (tPA)/urokinase plasminogen activator (uPA)/matrix metalloproteinase (MMP)-9 modulation in experimental ICH. Intracerebral hemorrhage was induced via the infusion of collagenase into the left basal ganglia of adult rats. Either memantine (20 mg/kg/day) or PBS was intraperitoneally administered 30 min after the induction of ICH, and, at daily intervals afterwards, for either 3 or 14 days. Hemorrhage volume decreased by 47% in the memantine group, as compared with the ICH-only group. In the memantine group, the numbers of TUNEL+, myeloperoxidase (MPO)+, and OX42+ cells decreased in the periphery of the hematoma. Memantine resulted in an upregulation of bcl-2 expression and an inhibition of caspase-3 activation. Memantine also exerted a profound inhibitory effect on the upregulation of tPA/uPA mRNA, and finally decreased the MMP-9 level in the hemorrhagic brain. In modified limb-placing test, the memantine-treated rats exhibited lower scores initially, and recovered more quickly and thoroughly throughout the 35 days of the study. Here, we show that memantine causes a reduction of hematoma expansion, coupled with an inhibitory effect on the tPA/uPA and MMP-9 level. Subsequently, memantine was found to reduce inflammatory infiltration and apoptosis, and was also determined to induce functional recovery after ICH.
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PMID:Memantine reduces hematoma expansion in experimental intracerebral hemorrhage, resulting in functional improvement. 1610 86

The effects of statins on gene expression of cerebral endothelial cells (ECs) in vivo have not been investigated after stroke. We developed a rapid double immunofluorescent staining protocol with antibodies against von Willebrand factor (a marker for endothelium) and glial fibrillary acidic protein (a marker for astrocytes) for laser capture microdissection to isolate single ECs in brain tissue of the rat. Using this protocol in combination with real-time PCR, we found that stroke significantly increased mRNA levels of protease-activated receptor 1 (PAR-1) and tissue factor (TF) in ECs isolated from ischemic cerebral microvessels compared with nonischemic vessels. Treatment of embolic stroke with recombinant human tissue plasminogen activator (rht-PA) 4 h after stroke further elevated PAR-1 mRNA levels nearly 1000-fold in the core and 500-fold in the boundary above the nonstroke group 30 h after stroke, while TF mRNA levels were elevated approximately 10 fold above the nonstroke group. Furthermore, stroke significantly increased matrix metalloproteinase (MMP) 2 and 9 mRNA levels in the ischemic core and boundary regions 6 and 30 h after stroke. Treatment with rht-PA-upregulated MMP2 expression in the ischemic boundary and core. Atorvastatin completely blocked rht-PA upregulation of the above genes, when atorvastatin in combination with rht-PA was administered 4 h after stroke. Monotherapy of atorvastatin 4 h after stroke did not significantly reduce expression of genes examined in the present study. These data provide evidence that atorvastatin reduces exogenous tPA-aggravated cerebral endothelial genes that mediate thrombosis and blood-brain barrier permeability, which could contribute to the beneficial effects of statins on thrombolytic treatment of acute stroke.
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PMID:Atorvastatin downregulates tissue plasminogen activator-aggravated genes mediating coagulation and vascular permeability in single cerebral endothelial cells captured by laser microdissection. 1617 9

Cigarette smoke exposure is a major determinant of adverse lung health, but the molecular processes underlying its effects on inflammation and immunity remain poorly understood. Therefore, we sought to understand whether inflammatory and host defense determinants are affected during subchronic cigarette smoke exposure. Dose-response and time course studies of lungs from Balb/c mice exposed to smoke generated from 3, 6, and 9 cigarettes/day for 4 days showed macrophage- and S100A8-positive neutrophil-rich inflammation in lung tissue and bronchoalveolar lavage (BAL) fluid, matrix metalloproteinase (MMP) and serine protease induction, sustained NF-kappaB translocation and binding, and mucus cell induction but very small numbers of CD3+CD4+ and CD3+CD8+ lymphocytes. Cigarette smoke had no effect on phospho-Akt but caused a small upregulation of phospho-Erk1/2. Activator protein-1 and phospho-p38 MAPK could not be detected. Quantitative real-time PCR showed upregulation of chemokines (macrophage inflammatory protein-2, monocyte chemoattractant protein-1), inflammatory mediators (TNF-alpha, IL-1beta), leukocyte growth and survival factors [granulocyte-macrophage colony-stimulating factor, colony-stimulating factor (CSF)-1, CSF-1 receptor], transforming growth factor-beta, matrix-degrading MMP-9 and MMP-12, and Toll-like receptor (TLR)2, broadly mirroring NF-kappaB activation. No upregulation was observed for MMP-2, urokinase-type plasminogen activator, tissue-type plasminogen activator, and TLRs 3, 4, and 9. In mouse strain comparisons the rank order of susceptibility was Balb/c > C3H/HeJ > 129SvJ > C57BL6. Partition of responses into BAL macrophages vs. lavaged lung strongly implicated macrophages in the inflammatory responses. Strikingly, except for IL-10 and MMP-12, macrophage and lung gene profiles in Balb/c and C57BL/6 mice were very similar. The response pattern we observed suggests that subchronic cigarette smoke exposure may be useful to understand pathogenic mechanisms triggered by cigarette smoke in the lungs including inflammation and alteration of host defense.
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PMID:Differential protease, innate immunity, and NF-kappaB induction profiles during lung inflammation induced by subchronic cigarette smoke exposure in mice. 1636 58

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

A growing body of evidence supports an obligatory role for intrafollicular prostanoids in the mechanism of ovulation. However, the prostanoid-dependent mediators of the follicular extracellular matrix degradation required for ovulation are unknown. The objectives of this study were to determine the cellular compartment(s) in which the gonadotropin surge-induced regulation of select extracellular matrix degrading enzymes and their cognate inhibitors occurs in bovine preovulatory follicles, and to test whether such regulation is blocked by intrafollicular administration of the prostanoid synthesis and ovulation inhibitor, indomethacin (INDO). Follicular fluid prostaglandin E2 concentrations were elevated in diluent-treated follicles before ovulation (24 h after GnRH injection), but the increase was blocked in INDO-treated follicles. Real-time PCR analysis revealed the specific follicular cell types where gonadotropin surge-induced increases in mRNA abundance for members of the matrix metalloproteinase/tissue inhibitor of metalloproteinase and plasminogen activator families occurred. INDO treatment increased thecal cell mRNA for tissue inhibitor of metalloproteinase-4 and its protein abundance in the apex of preovulatory follicles before ovulation, but suppressed granulosal cell mRNA and activity for tissue plasminogen activator in follicular fluid and the follicle apex. Plasmin activity was also suppressed in the follicular fluid of INDO-treated follicles. Effects of INDO injection on select matrix metalloproteinases were not observed. The results suggest that gonadotropin surge-induced regulation of tissue inhibitor of metalloproteinase-4 and tissue plasminogen activator may be prostanoid dependent, and support a potential role for increased tissue plasminogen activator expression and decreased tissue inhibitor of metalloproteinase-4 expression in the mechanism of ovulation.
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PMID:Effect of intrafollicular indomethacin injection on gonadotropin surge-induced expression of select extracellular matrix degrading enzymes and their inhibitors in bovine preovulatory follicles. 1651 96

Thrombolysis with tissue plasminogen activator (tPA) is the only pharmacotherapy available for cerebral ischemia. However, the use of tPA can increase the risk of hemorrhage due to blood-brain barrier (BBB) breakdown. Recent evidence suggests that increased activation of matrix metalloproteinases (MMPs) may be involved in this breakdown. This study examines the temporal profile of MMP-2 and -9 following tPA administration to ischemic rats. Male Sprague-Dawley rats were randomly assigned to one of four groups (Sham-tPA; Sham-Saline; Ischemia-tPA; Ischemia-Saline; group n = 6, total N = 120). Focal embolic ischemia was induced by middle cerebral artery occlusion through injection of an autologous clot. One hour post-surgery, tPA (10 mg/kg) or saline was delivered intravenously and animals were euthanized at 3, 6, 12, or 24 h after onset of ischemia. Infarct volume was measured by TTC staining; BBB components examined immunohistochemically; and MMP activation measured by gelatin zymography. Our results show that tPA significantly reduced infarct volumes (overall infarct volume-Sham-tPA: 5.80 +/- 4.55 [mean +/- SE]; Sham-Saline: 5.00 +/- 4.23; Ischemia-tPA: 186.1 +/- 73.45; Ischemia-Saline: 284.8 +/- 88.74; all P < 0.05). Treatment with tPA was also associated with the activation of MMP-9 at 6, 12, and 24 h following ischemia. No temporal changes were observed in MMP-2 activation, although tPA administration increased its activity compared to saline treatment. Analyses of immunohistochemistry showed that destruction of components of the BBB followed MMP-9 activation. Thus, increased MMP-9 activation may, in part, be responsible for the increases in hemorrhagic transformation reported with use of tPA. Our study is the first to demonstrate the temporal profile of MMP activation following thrombolysis with tPA in a model of thrombotic focal cerebral ischemia.
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PMID:Matrix metalloproteinase activation and blood-brain barrier breakdown following thrombolysis. 1662 94

Insulin-like growth factor-binding protein 5 (IGFBP-5) mediates involution of the mammary gland. The decrease in DNA content and mammary gland weight which accompanies involution was inhibited by prolactin (PRL) in wild-type but not transgenic mice expressing IGFBP-5. Phospho-STAT5 protein levels were significantly lower in IGFBP-5 transgenic mice during lactation suggesting that IGFBP-5 antagonises PRL signalling in the mammary epithelium. In contrast, phospho-STAT3 levels increased during involution to a similar extent in both wild-type and transgenic mice and were unaffected by PRL. PRL inhibited gene expression of matrix metalloproteinases (MMPs) 3 and 12 but not tissue plasminogen activator or plasmin in wild-type and transgenic animals. The effects of PRL on MMPs appear to be indirect since PRL failed to inhibit MMP-3, -7 or -12 expression in HC-11 cells or in a co-transfection including an activated PRL receptor, STAT5 and a MMP-3-luciferase reporter gene. PRL is a potent inhibitor, both of cell death, an effect which is suppressed by IGFBP-5, and of MMP expression, which is independent of the actions of IGFBP-5.
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PMID:Prolactin inhibits cell loss and decreases matrix metalloproteinase expression in the involuting mouse mammary gland but fails to prevent cell loss in the mammary glands of mice expressing IGFBP-5 as a mammary transgene. 1672 Jul 15


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