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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The fibrinolytic potential of the endothelial cells gives important antithrombotic properties to the vascular wall. Thrombosis is a frequent complication to atherosclerosis and other conditions where inflammatory mediators are present in the vascular wall. Inflammatory agents like lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF alpha) have been demonstrated to modulate the expression of fibrinolytic factors in cultured endothelial cells. In the present study the expression of tissue-type plasminogen activator (t-PA), urokinase plasminogen activator (u-PA) and plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) antigen in conditioned medium from cultured human umbilical vein (HUVEC) and human saphenous vein (HSVEC) endothelial cells was investigated under basal conditions and after stimulation with LPS, TNF alpha, interferon-gamma (IFN-gamma) or interleukin-6 (IL-6) alone or in combinations. Stimulation with LPS or TNF alpha increased the expression of PAI-1, u-PA and PAI-2 in HUVEC and HSVEC, while the t-PA response differed between the two cell types. The effects of TNF alpha were modulated by IFN-gamma but not by IL-6. The increased expression of u-PA after stimulation with TNF alpha was reduced by IFN-gamma. In contrast, TNF alpha-induced expression of PAI-2 was synergistically increased by addition of IFN-gamma. These effects of IFN-gamma represent additional mechanisms by which inflammatory mediators may turn the fibrinolytic potential of the endothelium in a prothrombotic direction.
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PMID:Interferon-gamma modulates the fibrinolytic response in cultured human endothelial cells. 777 58

We assayed urokinase plasminogen activator (uPA), tissue type plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) in 43 human brain tumors (predominantly astrocytic gliomas) and in histologically disease-free brain tissue resected with 21 of the tumors. Levels of uPA, tPA, and PAI-1, measured by enzyme-linked immunosorbent assay, varied widely among individuals in neoplastic and in normal tissue but did not correlate with age or sex. Pairwise comparison of neoplastic and normal tissue from 21 individuals revealed that mean tumor uPA level was elevated 6-fold (P < 0.001). Mean tumor tPA and PAI-1 were 2.5-fold greater than those of normal brain, but these differences were not statistically significant. Tumor uPA was elevated 2- to 30-fold in 16/21 paired samples (76%). In contrast, tumor tPA was elevated 2- to 22-fold in 7/21 (33%) of pairs, whereas tumor PAI-1 was 2- to 13-fold greater in 10/21 (48%) of pairs. Our results demonstrate that elevation of uPA content is frequent in astroglial tumors, as is the case in other major human cancers.
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PMID:Urokinase plasminogen activator is elevated in human astrocytic gliomas relative to normal adjacent brain. 805 1

Human colonic epithelium is exposed to varying levels of sodium butyrate, which is derived from the bacterial fermentation of dietary carbohydrate. Sodium butyrate has several effects on colonic tumor cells in vitro, including arrest of cell growth and differentiation. In the present study we have found that, in addition to a reduction in cellular proliferation, sodium butyrate induces the transient expression of plasminogen activator inhibitor type-1 (PAI-1) in the LIM 2405 human colonic tumor cell. Approximately 40% of the PAI-1 secreted is biologically active as judged by the formation of higher molecular weight, SDS-resistant complexes with urokinase plasminogen activator (uPA). The enhanced PAI-1 biosynthesis was accompanied by an increase in PAI-1 mRNA levels. During the same time period, the amount of secreted uPA remained relatively constant, but the level of cell associated uPA decreased slowly and was accompanied by a decrease in uPA mRNA levels. The uPA receptor is synthesized constitutively by these cells, and was down-regulated at both the protein and mRNA levels in response to sodium butyrate. The results demonstrate that sodium butyrate can alter the balance of components of the plasminogen activator system in a manner which favours net decreased plasminogen activator activity and suggests a role for sodium butyrate in the regulation of extracellular proteolysis.
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PMID:Sodium butyrate differentially modulates plasminogen activator inhibitor type-1, urokinase plasminogen activator, and its receptor in a human colon carcinoma cell. 810 11

A new chimeric plasminogen activator with high fibrin affinity was designed to bind fibrin and to initiate clot destruction, following activation by thrombin. The chimeric activator, 59D8-scuPA-T, was made from the Fab fragment of an anti-fibrin antibody (59D8) and a C-terminal portion of a thrombin-activable low molecular weight single-chain urokinase plasminogen activator, scuPA-T, obtained by deletion of Phe-157 and Lys-158 from low molecular weight single-chain urokinase-type plasminogen activator (scuPA) by site-directed mutagenesis. The chimeric molecule had a molecular mass of 91,000, a value consistent with one 59D8 light chain (M(r) = 27,000) and one 59D8 heavy-chain Fd fragment fused to low molecular weight scuPA (M(r) = 64,000). According to its design, 59D8-scuPA-T was activated by thrombin but not by plasmin, whereas the control chimeric molecule, 59D8-scuPA, was activated by plasmin but not by thrombin. When activated by thrombin, 59D8-scuPA-T converted plasminogen to plasmin. In vitro plasma clot lysis assays showed that 59D8-scuPA-T lysed clots performed by thrombin and that heparin and hirudin could prevent clot lysis. When incorporated as part of a thrombin-induced clot, only 59D8-scuPA-T was able to lyse the clot while 59D8-scuPA and high molecular weight scuPA were ineffective. Together these results demonstrate that 59D8-scuPA-T is a thrombin-activable plasminogen activator that offers selective thrombolysis of thrombin-rich clots over more established, aged clots, and may also act as an antithrombotic agent.
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PMID:Design and evaluation of a thrombin-activable plasminogen activator. 811 52

The pathophysiology of the cellular basis of radiation-induced demyelination and white-matter necrosis of the central nervous system (CNS) is poorly understood. Preliminary data suggest that tissue damage is partly mediated through changes in the proteolytic enzymes. In this study, we irradiated rat cervical spinal cords with single doses of 24 Gy of 18 MV photons or 20 MeV electrons and measured the levels of plasminogen activators at days 2, 7, 30, 60, 90, 120, 130 and 145 after irradiation, using appropriate controls at each time. Fibrin zymography revealed fibrinolytic bands representing molecular weights of 68,000 and 48,000 in controls and irradiated samples; these bands increased significantly at days 120, 130 and 145 after irradiation. Inhibition of these enzymatic bands with specific antibodies against tissue-type plasminogen activator (tPA) and amiloride, an inhibitor for urokinase plasminogen activator (uPA), confirmed that these bands were tPA and uPA. Enzymatic levels quantified by densitometry showed a twofold elevation in the levels of tPA and more than a tenfold increase in uPA after 120 days' irradiation. Activity of uPA was increased threefold by day 2 and increased steadily with time compared to nonirradiated control samples. Enzyme-linked immunosorbent assay (ELISA) also showed a threefold increase in the tPA content in the extracts of irradiated rat cervical spinal cords at days 120, 130 and 145. This study adds additional information to the proposed role of plasminogen activators in the pathogenic pathways of radiation damage in the CNS.
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PMID:Elevated levels of plasminogen activators in the pathogenesis of delayed radiation damage in rat cervical spinal cord in vivo. 818 13

Using immunohistochemistry and in situ hybridization, we have characterized the expression and localization of components of the plasminogen activator proteolytic cascade in an organotypic coculture system which consists of a "dermal" portion (human dermal fibroblasts throughout a collagen matrix) and a stratified, well-differentiated epidermal portion. Specifically, the following components were examined: the enzymes urokinase-type plasminogen activator and tissue-type plasminogen activator and their type 1 and type 2 inhibitors. Urokinase plasminogen activator mRNA and antigen were found predominantly in the least differentiated, basal keratinocytes; in some fields there was also faint deposition of antigen beneath the basal cells. The distribution of plasminogen activator inhibitor type 1 was similar to that of urokinase, except that inhibitor type 1 antigen deposition beneath the basal cells appeared more intense and uniform. In contrast to the results with urokinase plasminogen activator and inhibitor type 1, tissue plasminogen activator mRNA and antigen were localized focally in the suprabasal, i.e. more differentiated, keratinocytes. Plasminogen activator inhibitor type 2 mRNA and antigen were detected in most epidermal layers, but were more intense suprabasally and often spared the basal layer. These studies demonstrate that the same type of cell, i.e. the keratinocyte, can express different components of the plasminogen activator cascade depending on its state of differentiation. The change in expression of plasminogen activator cascade components with keratinocyte differentiation suggests distinct epidermal functions for these components, related to cell-matrix interaction and epidermal differentiation.
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PMID:Differential expression of plasminogen activators and their inhibitors in an organotypic skin coculture system. 827 Jun 42

Glomerular plasminogen activator inhibitor-1 (PAI-1) steady-state mRNA and bioactivity were increased after the induction of an augmented form of antiglomerular basement membrane (GBM) antibody glomerulonephritis. PAI-1 mRNA expression was noted at 6 h, peaking at 1 day, and although falling thereafter, remained higher than that of the control group through Day 17. PAI-1 mRNA expression correlated with glomerular PAI-1 bioactivity as determined by a functional tissue type plasminogen activator (t-PA) binding assay. Glomerular PAI-1 bioactivity, not detected in controls, increased to 1.4 +/- 0.3 ng/mg of glomerular lysate at 6 h and then decreased to 0.7 +/- 0.1 ng/mg of glomerular lysate by Day 6. The mRNA of the plasminogen activators (urokinase plasminogen activator), t-PA) either remained unchanged or declined through Day 1, with a slight increase in t-PA mRNA at Day 6. Interleukin-1 beta mRNA expression was maximal at 6 h, declining by Day 3. Transforming growth factor beta 1 (TGF-beta 1) mRNA began to increase at Day 1, was maximal at Day 6, and fell only slightly by Day 17. Epidermal growth factor mRNA decreased. The increase in PAI-1 mRNA and bioactivity, possibly induced early by the interleukin-1 beta response and perhaps later by the TGF-beta 1 response, was associated with striking glomerular capillary lumen fibrin accumulations on Day 1, which decreased and appeared to recanalize as the PAI-1 mRNA and bioactivity fell. The glomerular lesion continued to have some fibrin deposits even on Day 17 and, in addition, had changes of thickened GBM, suggestive of the early stages of diffuse glomerulosclerosis. The latter had a temporal relationship with the persisting increase in TGF-beta 1 and PAI-1 mRNA levels. These observations suggest the possibility that inhibition of enzymes capable of remodeling excessive extracellular matrix production may have contributed to the thickened GBM.
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PMID:Dysfunction of glomerular fibrinolysis in experimental antiglomerular basement membrane antibody glomerulonephritis. 832 70

In Vienna, Austria, health workers took blood samples from 16 healthy, nonsmoking 19-35 year old women before and after they began using a combined oral contraceptive (OC) (Gynovin) (30 mcg ethinyl estradiol and 75 mcg gestodene) to assess the OC's effects on blood coagulation and fibrinolysis and the effect of the estrogen component on endothelial cells. Fibrinogen levels increased significantly after OC use (283 mg/dl vs. 342 mg/dl after the 1st treatment cycle; p .005). These levels remained significantly higher (326 mg/dl and 339 mg/dl after the 2nd and 3rd treatment cycles; p .005 and .05, respectively). Thrombin antithrombin III complex (TAT) and prothrombin fragment F1+2 levels increased just minimally during OC treatment. Levels of fibrin split-product D-dimer, plasma tissue plasminogen activator (t-PA) activity, and plasmin-antiplasmin (PAP) complexes were significantly higher during all OC treatment cycles than they were before treatment. Active plasminogen activator inhibitor (PAI-1) antigen, t-PA, and urokinase plasminogen activator antigen levels fell significantly after OC treatment and remained low during OC treatment. Experiments with the culture of human umbilical vein endothelial cells showed that ethinyl estradiol did not significantly affect the tissue factor content or surface thrombomodulin activity of these endothelial cells (i.e., hemostatic regulatory activities). It also did not change the secretion of the fibrinolytic components t-PA and PAI-1. None of the women developed thrombosis. Even though these findings did not clearly show OC-induced hemostatic activation in this relatively small group of women, clinical researchers should still determine activation markers to monitor the activation state of blood coagulation in certain OC users, such as obese women and those who smoke cigarettes.
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PMID:Studies on oral contraceptive-induced changes in blood coagulation and fibrinolysis and the estrogen effect on endothelial cells. 839 73

We tested distinct variants of a human keratinocyte line (HaCaT) for the expression of tissue-type plasminogen activator (tPA)-specific mRNA, as well as cell surface-associated and secreted tPA. Cells of early passages (passage no. 22) only expressed urokinase plasminogen activator (uPA)- but not tPA-specific mRNA. Cells after prolonged culture (passage no. 44) expressed uPA- and tPA-specific mRNA, but did not release tPA in the extracellular space and did not display surface-associated tPA. HaCaT cells transformed with the c-Ha-ras oncogene (HaCaTras) showed both secreted and surface-associated tPA antigen. The secreted and the surface-associated plasminogen activator (PA)-activity of HaCaTras cells were in part inhibitable by anticatalytic anti-tPA antibodies, thus indicating that tPA contributes to extracellular and surface-associated plasminogen activation. Finally, we demonstrate that tPA secretion of HaCaT 44 cells can be induced by retinoic acid, most likely via interaction of retinoic acid with nuclear-associated retinoic acid-receptor(s).
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PMID:tPA of human keratinocytes: contribution to cell surface-associated plasminogen activation and upregulation by retinoic acid. 860 43

Previous studies have shown that high glucose levels and diabetes induce an elevation in protein kinase C (PKC) activity in vascular cells and tissues susceptible to diabetic complications. In addition, PKC activation has been shown to modulate vascular cell growth, permeability, and gene expression, processes thought to be involved in the development of vascular complications. Using two in vivo model systems, we have identified a novel inhibitor of diabetic vascular dysfunction, LY290181. LY290181 prevented glucose-induced increases in blood flow and permeability in rat granulation tissue and corresponding vascular changes in the retina, sciatic nerve, and aorta of diabetic rats. Tested for its ability to inhibit PKC-regulated processes, LY290181 inhibited phorbol ester-stimulated plasminogen activator activity in a dose-dependent manner in bovine retinal endothelial cells and in human dermal fibroblasts. In addition, LY290181 inhibited phorbol ester-stimulated activation of the porcine urokinase plasminogen activator (uPA) promoter (-4600/+398) linked to the chloramphenicol acetyltransferase (CAT) reporter gene (p4660CAT). More detailed analysis of the uPA promoter revealed that LY290181 inhibited phorbol ester-stimulated activation of the uPA phorbol response element (-2458/-2349) located upstream of the thymidine kinase promoter (puPATKCAT). LY290181 appears to inhibit uPA promoter activation by blocking phorbol ester-stimulated binding of nuclear proteins to the uPA PEA3/12-0-tetradecanoylphorbol 13-acetate responsive element (TRE). These results suggest that LY290181 may inhibit diabetes-induced vascular dysfunction by inhibiting transcription factor binding to specific PKC-regulated genes involved in vascular function.
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PMID:LY290181, an inhibitor of diabetes-induced vascular dysfunction, blocks protein kinase C-stimulated transcriptional activation through inhibition of transcription factor binding to a phorbol response element. 862 Oct 17


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