Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A quantitative method is described for measuring the amount of plasminogen activator produced by rat ovarian granulosa cells following exposure to hormones in vivo or in vitro. The results confirm the previously reported observation (Beers, W. H., Strickland, S., and Reich, E. (1975) Cell 6, (387-394) that granulosa cells in vivo produce increasing amounts of plasminogen activator as the time of ovulation approaches and that the enzyme is produced only be cells obtained from follicles destined to ovulate. Inactive cells can be stimulated in vitro by gonadotropins to produce plasminogen activator. This response is time- and dose-dependent, and results in an increase of intracellular and extracellular enzyme. Studies of the specificity of this response indicate that preparations of follicle-stimulating hormone are much more effective than corresponding preparations of luteinizing hormone. The effect of other pituitary hormones is also presented. Molecules other than gonadotropins are also capable of stimulating the cells to produce the enzyme. Prostaglandins E1 and E2 and analogues of cAMP effectively stimulated the cells to produce plasminogen activator, cGMP and its analogues and prostaglandins F1a and F2a were without effect as were the six steroids studied. The inactive compounds also did not inhibit the response of the cells to gonadotropins. The granulosa cell plasminogen activator has been analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and has an apparent molecular weight of 75,000. By this and other criteria, the granulosa cell enzyme is similar to one of the species of plasminogen activators obtained from cultures of simian virus 40-transformed rat embryo fibroblasts.
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PMID:Studies on the role of plasminogen activator in ovulation. In vitro response of granulosa cells to gonadotropins, cyclic nucleotides, and prostaglandins. 96 86

Tissue-type plasminogen activator (t-PA) reacts upon exposure to endothelium-derived relaxing factor (EDRF) by way of the enzyme's single free sulfhydryl (Cys-83) to form a stable S-nitrosothiol protein adduct. S-nitrosylation endows t-PA with potent vasodilatory and antiplatelet properties that are accompanied by elevations in intracellular cyclic GMP analogous to those induced by low molecular weight (e.g., S-nitroso amino acid) S-nitrosothiols. Moreover, this chemical modification does not adversely affect the catalytic efficiency of t-PA, the fibrin stimulation of this activity, the binding of t-PA to fibrinogen, or the interaction of the enzyme with its physiologic serine protease inhibitor, plasminogen-activator inhibitor type I. The coupling of vasodilatory, antiplatelet, and fibrinolytic properties in one molecule makes the S-nitrosylated t-PA a unique molecular species and may provide insight into the mechanisms by which the endothelium maintains vessel patency. These data also suggest a pharmacologic approach to treatment of thromboocclusive disorders.
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PMID:S-nitrosylation of tissue-type plasminogen activator confers vasodilatory and antiplatelet properties on the enzyme. 132 44

The nitrate derivatives in clinical usage have in vitro platelet inhibitor and therefore antiaggregant properties. As with EDRF, this effect is mediated, at least partially, by increased intraplatelet cGMP concentrations. There is a probable synergistic action with prostacyclin and its clinically stable analogues which exert their inhibitor effect via cGMP. The reality of an ex vivo inhibitor effect (after clinical administration) is more difficult to demonstrate. Some groups have reported prolonged bleeding times after administration of trinitrin. The interactions of nitrate derivatives with molecules used as platelet inhibitors, such as aspirin, require further study as do interactions with heparin (possible induction of resistance by a qualitative anti-thrombin III deficiency) and thrombolytics (increased clearance of tissue type plasminogen activator).
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PMID:[Nitrate derivatives and hemostasis: fundamental concepts and clinical implications]. 153 Apr 30

Human subcultures (third passage) of glomerular visceral epithelial cells (VEC) isolated from one month old kidney were successfully transfected by two recombinant plasmids containing the cloned oncogenes from the simian virus 40 large T antigen and H-ras gene. One postcrisis cell clone (56/10 A1) was selected, propagated and characterized. One hundred percent of the 56/10 A1 cells (current passage greater than 100th; doubling time 30 hrs) expressed the nuclear T-SV40 antigen assayed by IF; the cells failed to express H-ras (RNA blot analysis). Immortalized cells were morphologically and phenotypically compared to parental cell type (third passage). Phenotypic characterization of the 56/10 A1 cells was achieved using indirect immunofluorescence (IF) and immunogold silver staining coupled to bright field and epipolarization microscopy. Both parental and 56/10 A1 cells displayed positivity for cytokeratin, CALLA and PHM5, whereas von Willebrand factor was not detected in the two cell types. Since we have previously shown that human glomerular epithelial cells in culture synthetize plaminogen activator (PA) related compounds, we investigated the secretion pattern of these products in parental and transfected cells. Zymographic analysis of secreted PA related compounds revealed production of free urokinase (u-PA) and type 1 plasminogen activator inhibitor (PAI-1) complexed to tissular plasminogen activator (t-PA). Finally, in the transfected cells, increased cGMP generation under atrial natriuretic factor (ANF) stimulation agreed with previous work performed on nontransfected human VEC. In conclusion, the establishment of a human permanent cell line which retains most of the phenotypic features of parental glomerular visceral epithelial cells should represent a new tool to study human glomerular cell functions.
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PMID:Stable cell line of T-SV40 immortalized human glomerular visceral epithelial cells. 166 15

Macrophages incubated with complexed or aggregated IgE released beta-glucuronidase (beta-G) within 30 min. In contrast in the presence of aggregated or complexed IgG, macrophages liberated equivalent amount of beta-G only after 6 h incubation. In addition the rapid macrophage stimulation induced by aggregated IgE was also followed by a faster 3H-glucosamine incorporation when compared to the delayed activation caused by aggregated IgG. However, macrophages stimulated either by IgG or by IgE oligomers produced the same percentage of plasminogen activator at 24 h. In contrast, while the interaction between macrophages and aggregated IgE was only followed by a peak of cyclic GMP and a beta-G release during the first 30 min of incubation, the interaction between macrophages and IgG oligomers was accompanied by a simultaneous increase of cyclic GMP and AMP nucleotides and by an absence of beta-G exocytosis. Moreover, the beta-G release induced by aggregated IgE was increased when macrophages were preincubated with aggregated IgG. This additive effect was not observed in the reverse situation. Finally macrophages activated by IgG oligomers were demonstrated to exert a cytotoxic effect on tumour cells and to kill schistosomula in the presence of a low level of complement. Taken together these results underline the peculiar ability of aggregated or complexed IgE to trigger rapidly the macrophage activation compared to aggregated IgG and can explain the important role of complexed IgE in some macrophage dependent cytotoxicity mechanisms (i.e. in parasitic diseases).
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PMID:Macrophage triggering by aggregated immunoglobulins. II. Comparison of IgE and IgG aggregates or immune complexes. 608 35

Macrophages from various sources can be stimulated by a variety of substances to secrete a range of inflammatory mediators and degradative enzymes. The mechanisms involved in the activation and secretory processes are unknown, However, recent evidence suggests that cyclic AMP may play a role in the regulation of neutral protease secretion. Thus, it has been shown that agents known to increase intracellular cyclic AMP levels (cyclic AMP analogues, phosphodiesterase inhibitors, prostaglandin E1 and E2, catecholamines, cholera toxin and, indirectly, glucocorticosteroids) inhibit the secretion of the neutral protease plasminogen activator. It is speculated that macrophage activation may also initiated by changes in the steady-state levels of cyclic nucleotides. A decrease in intracellular cyclic AMP and/or an increase in cyclic GMP levels would favour secretion. It is possible that these changes could be brought about by the action of various stimuli to modify the capacity of the macrophage to synthetize or degrade cyclic nucleotides.
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PMID:Cyclic nucleotides, possible intracellular mediators of macrophage activation and secretory processes. 626 14

Endothelial cells are central in fibrinolysis because of their high production of both activators (t-PA, uPA) and inhibitors (PAI-1). The t-PA and PAI-1 synthesis could be regulated by signals transduction at several cellular levels. The purpose of this in vitro study, on cultured endothelial cells, was to explore the receptor/second messenger regulation of the t-PA and PAI-1 synthesis. Quiescent confluent human umbilical vein endothelial cells, cultured in passage 1, were exposed to different test substances. Samples from the conditioned medium were collected after 16 and 24 h and analysed for t-PA and PAI-1 antigen. All data presented were related to the data from control dishes (= 100%), in the same experiment. The results from the present study (mean +/- 95% confidence interval) demonstrated the following. (1) Forskolin, with a documented direct cAMP-inducing effect, decreased the basal PAI-1 production to 61 +/- 15%, and Na-nitroprusside, with a documented cGMP-inducing effect, increased the basal PAI-1 production to 141 +/- 38% without affecting the basal t-PA production. The surface receptor agonists isoprenalin or ephedrine, which indirectly affect adenylate cyclase, had no effect on t-PA or PAI-1 production. (2) Phorbolester (PMA), which directly activates proteinkinase C (PKC), increased the basal t-PA and PAI-1 production to 350 +/- 71%, and 163 +/- 35% respectively. (3) Thrombin, but not endothelin-1 (ET-1), increased the basal t-PA and PAI-1 production to 195 +/- 34% and 136 +/- 18%, respectively, indicating an PKC-mediated thrombin effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Complex intracellular signal transduction regulates tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1) synthesis in cultured human umbilical vein endothelium. 756 35

The modulation of the induced acute release of tissue-type plasminogen activator (t-PA) and of von Willebrand factor (vWF) by compounds affecting cyclic nucleotide levels was studied, using an isolated rat hindleg perfusion system. Platelet-activating factor (PAF; 5 nM) or bradykinin (0.8 microM) were used to induce release of t-PA and vWF. The guanylate cyclase activators sodium nitroprusside and atrial natriuretic factor reduced the induced release of t-PA and vWF. Release was not affected by inhibiting nitric oxide production with NG-nitro-L-arginine. The effects of nitroprusside and atrial natriuretic factor could not be reproduced by infusion of 8-bromo-cGMP. The adenylate cyclase activator forskolin had no effect on bradykinin-induced release of t-PA and vWF, reduced PAF-induced t-PA release, but potentiated PAF-induced vWF release. These modulatory effects were only partially mimicked by infusion of 8-bromo-cAMP. None of the compounds tested was able to induce the release of t-PA or of vWF in the absence of stimulation by bradykinin or platelet-activating factor. Cyclic nucleotides can thus modulate, but not induce, the acute release of t-PA and vWF from perfused rat hindlegs.
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PMID:The role of cyclic nucleotides in the release of tissue-type plasminogen activator and von Willebrand factor. 809 63

In vitro prostacyclin (PGI2) and nitric oxide (NO) synergise in their anti-aggregatory actions on blood platelets. Presently, we have studied an interaction of molsidomine (ML--pro-drug for the NO-donor SIN-1) and PGI2 in 20 patients with peripheral arterial disease (PAD) on the plasma fibrinolytic system and platelet aggregability. A synergism of these drugs in their fibrinolytic action as measured by shortening of euglobulin clot lysis time (ECLT) and in their anti-platelet action as measured by an increase in the ratio of free platelets to platelet aggregates was observed. It seems that PGI2 and ML activated the fibrinolytic system by two independent mechanisms i.e. by a PGI2-induced direct release of pro-fibrinolytic t-PA from endothelial cells and by a ML-induced suppression of the release of anti-fibrinolytic PAI-1 from platelets. This may constitute a basis for the synergism. A synergism between PGI2 and ML in their anti-platelet action seems to be rooted in the potentiation by cyclic-GMP on the anti-aggregatory action of cyclic-AMP in platelets. On the other hand, no synergism between PGI2 and ML was observed in their hypotensive effects as measured by systolic and diastolic arterial blood pressure. It may well be that the synergism in fibrinolytic and anti-platelet actions between stimulators of adenylate and guanylate cyclases accompanied by a lack of synergism in their hypotensive actions may allow reduction of the therapeutic doses of either stimulator, thus avoiding hazards of their hypotensive side effects.
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PMID:Prostacyclin and molsidomine synergise in their fibrinolytic and anti-platelet actions in patients with peripheral arterial disease. 843 99

Tissue-type plasminogen activator (tPA) is an endothelium-derived vasoactive substance which is released to the blood stream by exercise, blood occlusion, and desmopressin (DDAVP). The increased capacity of the plasma tPA level raised by these factors is thought to reflect in vivo endothelial function. On the other hand, endothelial dysfunction has been reported in patients with hypercholesteremia as well as in those with diabetes mellitus. Therefore, diabetic patients with hypercholesteremia were administered 5 mg of simvastatin daily for one month and plasma tPA responses evoked by DDAVP were examined before and after treatment for hypercholesteremia. While the treatment of simvastatin for one month significantly reduced serum cholesterol levels from 257 +/- 12 mg to 206 +/- 10 mg (no change in HbA1c was observed during the study), plasma tPA levels and % delta vWF (von Willebrand factor) following DDAVP infusion significantly increased from 11.4 +/- 1.2 ng/ml to 13.4 +/- 1.4 ng/ml and from 69.3 +/- 23.4% to 126.5 +/- 47.4%, respectively. However, neither increase in plasma levels of guanosine 3', 5'-cyclic monophosphate (cGMP) nor change in the depressive response of blood pressure was observed following DDAVP infusion after the treatment of simvastatin. In addition, no change in urinary albumin excretion rate was observed with the treatment of hypercholesteremia. Therefore, it was suggested that improvement in hypercholesteremia may ameliorate vascular endothelial dysfunction in diabetic patients with hypercholesteremia and that hypercholesteremia may enhance endothelial dysfunction in these patients.
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PMID:[Effect of hypercholesteremia on vascular endothelial function and albumin excretion rate in patients with diabetes mellitus]. 895 5


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