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

Defibrotide is a polydeoxyribonucleotide sodium salt with antithrombotic properties. These properties have been attributed to its profibrinolytic activity [increase of tissue plasminogen activator (t-PA) activity, concomitant decrease of that of plasminogen activator inhibitor (PAI)], but there could conceivably be other factor(s). To look for these, we studied Defibrotide in a thrombosis model (pulmonary thromboembolism in mice) in which free radicals play a pivotal role. Defibrotide was found to be active after both intravenous and oral administration. Defibrotide behaved in vitro like a scavenger of H2O2 but not of O2.- in cell-free systems. Defibrotide added in vitro to cellular systems decreased the stimulated release of beta-glucuronidase from polymorphonuclear cells (PMNs), the luminol chemiluminescence induced by oxygen species generated by stimulated PMNs and the generation of O2.- from stimulated macrophages. We think that the antithrombotic activity of Defibrotide is based on other factor(s) in addition to profibrinolytic activity, i.e., some scavenger activity and desensitization of cells involved in thrombus formation must also be taken into account.
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PMID:A novel insight into the mechanism of the antithrombotic action of defibrotide. 133 34

Cultured confluent human umbilical vein endothelial cells were incubated with new-breviscapine (NB), a flavonoid consisting of 4-OH-scutellarin-7-O-glucuronide (C33H30O18) and FeCl3, MgCl2, and CaCl2, which is first extracted from Erigeron breviscapus (Vant) Hand-Mazz in China, 0, 6.25, 12.5, 25, 50, 100, and 1,000 micrograms.ml-1. The releases of tissue-type plasminogen activator (t-PA), and epoprostenol (Epo) from endothelial cells were stimulated by NB, but no significant effect of plasminogen activator inhibitor (PAI) activity was seen. NB 25-1,000 micrograms.ml-1 induced a production of thrombomodulin (TM) within the cells, an expression of TM on the surface of the cells, and a release of TM from the cells. Our data provide a new evidence that NB is a stimulant to fibrinolysis and anticoagulation of endothelial cells.
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PMID:Effect of new-breviscapine on fibrinolysis and anticoagulation of human vascular endothelial cells. 133 21

Receptor-mediated endocytosis of tissue-type plasminogen activator (t-PA)-plasminogen activator inhibitor type 1 (PAI-1) complexes results in their clearance by Hep G2 cells. After complexes are internalized, the t-PA component is degraded. However, neither the locus of intracellular catabolism nor the fate of PAI-1 has been elucidated. To characterize these aspects of t-PA-PAI-1 catabolism, the subcellular distribution of a prebound cohort of ligand molecules was delineated after internalization at 37 degrees C. 125I-t-PA.PAI-1 and t-PA.125I-PAI-1 were compared in separate experiments. After ligand uptake, intracellular vesicles were separated on density gradients. Internalized 125I-t-PA.PAI-1 concentrated initially in endosomes. After 20 minutes of uptake, the complex began to appear in lysosomes. Subsequently, low molecular weight labeled ligand fragments were detected in culture media. A panel of lysosomotropic agents, including primaquine, chloroquine, ammonium chloride, and a combination of leupeptin and pepstatin A, inhibited degradation. When t-PA.125I-PAI-1 rather than 125I-t-PA.PAI-1 was internalized, strikingly different results were observed. Although the kinetics of internalization and the intracellular itinerary were indistinguishable for the differently labeled complexes, the 125I-PAI-1 component of t-PA.125I-PAI-1 resisted rapid degradation. After a rapid loss of t-PA, the 125I-PAI-1 moiety persisted in lysosomes for up to 180 minutes. Thus, internalized t-PA.PAI-1 is targeted to lysosomes in which PAI-1 is relatively more stable than t-PA.
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PMID:Endocytosis and lysosomal delivery of tissue plasminogen activator-inhibitor 1 complexes in Hep G2 cells. 133 99

Two plasminogen activators (PAs): tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), as well as the type-1 plasminogen activator inhibitor (PAI-1) are synthesized and secreted by rat astrocytes. Preliminary studies suggest that PA activity plays a role in astrocyte development and differentiation. We have examined the regulation of the PA system by the cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) in purified rat astrocyte cultures. PKA activity was increased by exposing cultured astrocytes to forskolin or dibutyryl cyclic AMP, whereas PKC activity was stimulated with phorbol-12-myristate 13-acetate (PMA). Activation of both second-messenger pathways produced a time- and dose-dependent increase in the total PA activity. However, based on SDS-PAGE/zymography we found that forskolin increased t-PA activity and reduced u-PA activity, whereas PMA treatment caused a significant increase in u-PA activity without altering t-PA activity. Reverse zymography analysis revealed that astrocyte PAI-1 activity is decreased by forskolin and increased by PMA. Together, these results demonstrate that the components of the PA system in rat astrocytes are independently and reciprocally regulated by PKA and PKC. Our findings raise the possibility that the plasminogen activator system could be involved in some of the actions of growth factors and/or neuromodulators that modulate PKC or PKA in astrocytes.
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PMID:Regulation of plasminogen activators and type-1 plasminogen activator inhibitor by cyclic AMP and phorbol ester in rat astrocytes. 133 67

The concentrations of tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA) and plasminogen activator inhibitor (PAI-1) have been determined in endometrial curettings obtained from 46 subfertile women during proliferative, early or late secretory phases of the menstrual cycle. t-PA activity and antigen concentrations was significantly higher (P < 0.001) in late secretory endometrium than in proliferative or early secretory endometrium. Higher concentrations of PAI-1 antigen (P < 0.05) were also noted in late secretory phase than in proliferative and early secretory endometrium. However, u-PA concentration was not significantly different and no PAI activity could be demonstrated in the menstrual phases studied. Zymography studies confirmed the presence of both t-PA and u-PA in the endometrium. Ovarian hormonal patterns may therefore influence the activity of plasminogen activators especially of t-PA in the endometrium during various phases of the menstrual cycle.
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PMID:Concentration of plasminogen activators and inhibitor in the human endometrium at different phases of the menstrual cycle. 133 23

mRNA levels for urokinase type plasminogen activator (uPA), tissue type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2) were examined in human diploid (neonatal foreskin) fibroblasts grown in 200-ml microcarrier suspension culture. Four different substrates were used. These included gelatin-coated polystyrene plastic, DEAE-dextran, glass-coated polystyrene plastic and uncoated polystyrene plastic. Our previous studies have shown that culture fluids from diploid fibroblasts grown on DEAE-dextran contained higher levels of plasminogen-dependent fibrinolytic activity than culture fluids from the same cells grown on other substrates. The increased plasminogen activator activity was due largely to elevated amounts of tPA (In Vitro Cell. Develop. Biol. 22: 575-582, 1986). The present study shows that there is a corresponding elevation of tPA mRNA in diploid fibroblasts cultured on DEAE-dextran relative to the other substrates. There does not appear to be any difference in uPA mRNA or in mRNA for PAI-1 or PAI-2 produced by the same cells on the four substrates. These data suggest that the influence of the substrate on plasminogen activator production is mediated at the genetic level.
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PMID:Expression of plasminogen activator and plasminogen activator inhibitor mRNA in human fibroblasts grown on different substrates. 136 69

The human hepatoma HuH-7 cell line was shown to constitutively express both a plasminogen activator (PA) and a plasminogen activator inhibitor (PAI). Four sublines of the HuH-7 cell line were analyzed and found to express differing amounts of both PA and PAI. The plasminogen activator produced by these cells was identified as urokinase based upon molecular weight, inhibition of activity with anti-UK but not anti-t-PA antibodies, adherence to an anti-UK affinity column and by Northern blotting demonstrating positive hybridization with the cDNA for UK, but not with the t-PA cDNA. The inhibitor produced by HuH-7 cells was identified as PAI-1 by molecular weight, immunoblotting techniques, adherence to an anti-PAI-1 affinity column, and by Northern blotting demonstrating positive hybridization with the cDNA for PAI-1, but not with the PAI-2 cDNA. The expression of both UK and PAI-1 by HuH-7 cells could be modulated by cytokines known to influence the acute phase response. The addition of interleukin-1 (IL-1) induced the expression of both UK and PAI-1. The increase of PAI-1 was due to an increase in amount of the PAI-1 mRNA. The presence of both interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF) also increased UK and PAI-1 levels, although not as dramatically as IL-1. The addition of IL-1 together with IL-6 produced a slight synergistic response with respect to PAI-1 expression. This suggests that PAI-1 is able to respond to mediators which aid in the induction of the acute phase response. These studies demonstrate that cells of liver origin are able to produce components of the fibrinolytic system. The synthesis of these components can be altered by inflammatory mediators and thus may be involved in hepatic regulation of fibrinolysis in both normal and diseased states.
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PMID:Human HuH-7 hepatoma cells express urokinase and plasminogen activator inhibitor-1: identification, characterization and regulation by inflammatory mediators. 137 1

Physicians at the Medical Clinic at the Johannes Gutenberg University in Mainz, Germany, compared data on 6 18-35 year old healthy women who took low-dose estrogen oral contraceptives (OCs) with data on 10 healthy women of same age who did not take OCs and with data on 12 18-35 year old males to examine gender differences of the coagulation system, endogenous fibrinolytic activity, and platelet aggregation under normal conditions and immediately after spiroergometric exercise beyond the anaerobic threshold. This type of exercise considerably boosted tissue plasminogen activator (t-PA) in both men and women (1.6-5.5 IU/ml and 1.8-5.3 IU/ml, respectively; p .005). The increase was not as high in women using the low-dose estrogen OCs as it was for men and both groups combined, however; but the increase was still significant (1.5-3.8 IU/ml; p .005). Plasma lactate levels were 1.1 mmol/l in men and 0.5 mmol/l in both female groups and rose significantly in all 3 groups (about 5.5 mmol/l for men and about 2.5 mmol/l for women; p .001). Exercise beyond the anaerobic threshold did not change plasminogen activator inhibitor-I activities. A marked fall in the ED50 values for adenosine diphosphate (ADP) in men indicated considerable enhancement of platelet activity during exercise (p .05). ADP ED50 values did not change significantly in either women's groups. Yet women who took the OCs had a lower ED50 for ADP than both men and women not taking the OCs, suggesting they were more susceptible to platelet aggregation under control conditions and after exercise. These findings indicated a considerable gender difference in platelet aggregation and activation of the endogenous fibrinolytic system both at rest and during exercise. It was also pointed out that women taking OCs are at even greater risk of developing thrombosis than women not taking OCs.
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PMID:Increase in endogenous fibrinolysis and platelet activity during exercise in young volunteers. 137 84

Complexes between 125I-labeled urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1) bound to purified alpha 2-macroglobulin (alpha 2M) receptor (alpha 2MR)/low density lipoprotein receptor-related protein (LRP). No binding was observed when using uPA. The magnitude of uPA.PAI-1 binding was comparable with that of the alpha 2MR-associated protein (alpha 2MRAP). Binding of uPA.PAI-1 was blocked by natural and recombinant alpha 2MRAP, and about 80% inhibited by complexes between tissue-type plasminogen activator (tPA) and PAI-1, and by a monoclonal anti-PAI-1 antibody. In human monocytes, uPA.PAI-1, like uPA and its amino-terminal fragment, bound to the urokinase receptor (uPAR). Degradation of uPAR-bound 125I-uPA.PAI-1 was 3-4-fold enhanced as compared with uncomplexed uPAR-bound uPA. The inhibitor-enhanced uPA degradation was blocked by r alpha 2MRAP and inhibited by polyclonal anti-alpha 2MR/LRP antibodies. This is taken as evidence for mediation of internalization and degradation of uPAR-bound uPA.PAI-1 by alpha 2MR/LRP.
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PMID:Purified alpha 2-macroglobulin receptor/LDL receptor-related protein binds urokinase.plasminogen activator inhibitor type-1 complex. Evidence that the alpha 2-macroglobulin receptor mediates cellular degradation of urokinase receptor-bound complexes. 137 33

Parotid saliva from 12 healthy volunteers was collected prior to and after 5 and 25 min of stimulation at a constant flow rate of 0.25 or 1.0 ml min-1. In the salivary samples the concentrations of tPA (tissue-type plasminogen activator), PAI-1 (plasminogen activator inhibitor type-1), albumin and total protein were determined and the activity of amylase, tPA and PAI assessed. Presence of both tPA and PAI-1 antigen was demonstrated in all samples, and in unstimulated saliva the ratio between the activator and its inhibitor was 1:7. Upon stimulation we found a significantly increased concentration of PAI-1, a less pronounced increase in tPA concentration, unchanged amylase and total protein levels and significantly decreased albumin concentration. tPA activity was significantly reduced after prolonged stimulation which had no effect on PAI activity. In stimulated saliva a significant positive correlation between concentration of tPA and PAI-1 was demonstrated. Stimulation with citric acid had no effect on output of albumin which is passively filtered from blood, whereas the increase in flow rate corresponded to the significantly increased secretion rate of total protein and amylase which is secreted by gland cells. The secretion pattern of tPA and PAI-1 differed significantly from that of albumin in showing markedly increased output rate during the stimulation period, and the relative increase in output of PAI-1 was significantly higher than that of amylase and total protein. Thus, the results from this study suggest an active release of both tPA and its main inhibitor PAI-1 into saliva.
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PMID:Increased release of tissue plasminogen activator and its inhibitor in human parotid saliva upon stimulation. 138 46


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