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

A placebo-controlled double-blind study of patients undergoing cardiopulmonary bypass was conducted, comparing the effects of dexamethasone and a placebo on the activation of the plasmatic systems and blood cells and on the postoperative course after cardiopulmonary bypass. In the placebo group two patterns of blood activation could be distinguished. From the start of bypass, blood-material interaction caused an increase in complement C3a and elastase concentration. After release of the aortic cross-clamp, a statistically significant increase was observed in tumor necrosis factor, leukotriene B4, and tissue plasminogen activator activity (p less than 0.01, p less than 0.05, p less than 0.05, respectively). Dexamethasone treatment was not able to inhibit complement activation and elastase release during cardiopulmonary bypass. However, dexamethasone treatment effectively inhibited the increase in tumor necrosis factor, leukotriene B4, and tissue plasminogen activator activity after release of the crossclamp (p less than 0.01 compared with the placebo group). In the postoperative period the patients in the placebo group had hyperthermia and hypotension and required considerable intravenous fluid administration and cardiotonic treatment. The dexamethasone-treated patients, however, showed normothermia (p less than 0.01), had significantly higher blood pressures (p less than 0.01) without supportive treatment, and consequently were in the intensive care unit for a shorter period of time. We conclude that dexamethasone prevents the hemodynamic instability after cardiopulmonary bypass and thus improves the postoperative course by inhibition of the leukocyte and tissue plasminogen activator activity generated after release of the aortic crossclamp.
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PMID:Inhibition by dexamethasone of the reperfusion phenomena in cardiopulmonary bypass. 830 85

In a placebo-controlled double-blind study on patients undergoing cardiopulmonary bypass (CPB) we studied the inhibiting effects of dexamethasone, a high dose of methylprednisolone, and a low dose of prednisolone on the inflammatory reaction induced by CPB. During CPB two episodes of blood activation were noticed. First, the blood-material interaction caused a significant increase in complement C3a and elastase concentrations after the start of bypass (p less than 0.01). Secondly, the reperfusion of the ischemic heart, lungs, and peripheral tissue, after release of the aortic cross-clamp, caused an additional increase in C3a and elastase concentration and a statistically significant increase in leukotriene B4 (LTB4) concentration and tissue plasminogen activator (t-PA) activity (p less than 0.01, p less than 0.05, respectively). Dexamethasone treatment effectively inhibited the increase in LTB4 concentration and t-PA activity after release of the cross-clamp (significant differences to the placebo group, p less than 0.01, p less than 0.05, respectively). High-dose methylprednisolone treatment was almost as effective as dexamethasone treatment, whereas low-dose prednisolone treatment was less effective than methylprednisolone in the inhibition of the inflammatory mediators (DM greater than MP greater than P). None of the corticosteroid regimens was able to inhibit the increase in complement C3a and elastase. We therefore conclude that corticosteroids do not have an effect on complement activation during CPB. However, leukocyte activation and t-PA activity after release of the aortic cross-clamp are effectively inhibited by corticosteroid treatment, in a dose-dependent way. The inhibition of this inflammatory reaction will have a favourable effect on the postoperative course in patients who have undergone CPB.
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PMID:The role of different types of corticosteroids on the inflammatory mediators in cardiopulmonary bypass. 171 73

We have reported previously that incubation of HTC rat hepatoma cells with the synthetic glucocorticoid dexamethasone causes a 90% decrease in tissue-type plasminogen activator (tPA) activity secondary to a 4-fold increase in plasminogen activator inhibitor-1 (PAI-1) mRNA accumulation. Dexamethasone also induces a modest and transient increase in tPA mRNA. The cyclic nucleotide analog 8-bromo-cAMP (cA) causes a greater than 50-fold increase in PA activity, the result of a 90% decrease in PAI-1 and a sustained 2-fold increase in tPA mRNA accumulation. Dexamethasone and cA in combination cause a 150-fold increase in PA activity, the result of an 80% decrease in PAI-1 and a synergistic 15-fold increase in tPA mRNA. To determine the mechanism of this complex hormonal regulation, we have examined rates of synthesis and decay of PAI-1 and tPA mRNAs. Here we report that dexamethasone induces a 5-fold increase in PAI-1 gene transcription and does not significantly alter PAI-1 message decay; PAI-1 mRNA has a half-life of about 4 h in both untreated and dexamethasone-treated cells. In contrast, cA regulates PAI-1 mRNA by both decreasing the rate of PAI-1 gene transcription by 60% and accelerating the rate of PAI-1 message decay. Regulation of tPA by cA, both alone and in combination with dexamethasone, occurs primarily at the level of transcription. Dexamethasone and cA-induced tPA mRNA has a half-life of 2.75 h; tPA mRNA degradation is significantly inhibited by either cycloheximide or actinomycin-D.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transcriptional and posttranscriptional regulation of type 1 plasminogen activator inhibitor and tissue-type plasminogen activator gene expression in HTC rat hepatoma cells by glucocorticoids and cyclic nucleotides. 173 71

HTC rat hepatoma cells synthesize and secrete both tissue-type plasminogen activator (tPA) and type 1 plasminogen activator-inhibitor (PAI-1). Incubation with the synthetic glucocorticoid dexamethasone causes a rapid decrease in tPA activity which is secondary to a 5-fold increase in PAI-1 antigen and activity. Paradoxically, dexamethasone increases tPA antigen by 50%. We have analyzed HTC cell RNA by Northern and slot blot analysis, using as probes radiolabeled human PAI-1 and rat tPA cDNAs. HTC cells have a single species of PAI-1 mRNA of approximately 3.2 kilobases, which is increased 4-fold upon incubation with dexamethasone. Maximal induction occurs after 8-10 h of incubation. Half-maximal induction occurs at 5 nM dexamethasone. Dexamethasone also transiently increases the 2.8 kilobase tPA mRNA. The protein synthesis inhibitor cycloheximide does not affect accumulation of PAI-1 mRNA and does not block its induction by dexamethasone. In contrast, cycloheximide alone causes an increase in tPA mRNA, and in combination with dexamethasone, no further increase is observed. Induction of both mRNAs is prevented by actinomycin D. We conclude that the dexamethasone-induced increase in HTC cell PAI-1 activity and antigen is the result of a direct effect on accumulation of PAI-1 mRNA.
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PMID:Glucocorticoid induction of plasminogen activator and plasminogen activator-inhibitor messenger RNA in rat hepatoma cells. 246 9

Primary cultures of rat hepatocytes produce tissue-type plasminogen activator (tPA) and plasminogen activator-inhibitor type 1 (PAI-1). Incubation of hepatocytes with 50 microM 8-(4-chlorophenylthio)cAMP (CPT-cAMP) results in a 4-fold increase in tPA activity, whereas the synthetic glucocorticoid dexamethasone (1 microM) causes a more than 90% decrease. In combination, dexamethasone completely overcomes the CPT-cAMP effect and markedly decreases PA activity. PAI-1 is induced by both CPT-cAMP and dexamethasone, and the effects of these agents are additive. Accumulation of tPA mRNA is increased more than 4-fold by CPT-cAMP and is greatly decreased by incubation with dexamethasone. Dexamethasone in combination with CPT-cAMP totally blocks this cAMP effect. The protein synthesis inhibitor cycloheximide does not prevent either the dexamethasone-induced decrease or the CPT-cAMP-induced increase in tPA message and, in fact, augments the cAMP-induced increase in tPA mRNA. Hepatocyte PAI-1 mRNA levels are increased 2-fold by incubation with either CPT-cAMP or dexamethasone; in combination, these effectors cause a 4-fold increase in PAI-1 mRNA. Cycloheximide alone causes a marked increase in PAI-1 mRNA, but does not block the induction by either CPT-cAMP or dexamethasone. We conclude that incubation of hepatocytes with CPT-cAMP induces tPA activity by increasing tPA mRNA accumulation and that dexamethasone causes a decrease in tPA activity by both decreasing tPA mRNA and increasing PAI-1 mRNA and activity. Concomitant protein synthesis is not required for the regulation of tPA or PAI-1 mRNA by either CPT-cAMP or dexamethasone, indicating a primary effect of these agents on gene transcription or mRNA stability.
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PMID:Glucocorticoid and cyclic nucleotide regulation of plasminogen activator and plasminogen activator-inhibitor gene expression in primary cultures of rat hepatocytes. 253 89

The nature of vascular permeability factor (VPF) activity derived from serum-free conditioned medium containing cultured human malignant glial tumors has been further investigated. A 1000-fold purification was accomplished by sequential heparin-Sepharose affinity chromatography and high-performance liquid chromatography gel filtration chromatography steps. Vascular permeability factor activity falls into a molecular weight range of 41,000 to 56,000 D. Activity is bound to hydroxylapatite, carboxymethyl-Sepharose, phenyl-Sepharose, and heparin-Sepharose, whereas little or no activity was bound to diethylaminoethyl-Sephacel. Vascular permeability factor activity is trypsin- and pepsin-sensitive but is unaffected by treatment with ribonuclease A. This suggests that VPF is a hydrophobic, positively charged (cationic) polypeptide with a potentially biologically significant affinity for heparin. As most proteins are negatively charged (anionic) and have no affinity for heparin, a significant advantage was gained by performing these purification steps. The activity of VPF is not inhibited by coinjection of conditioned medium with soybean trypsin inhibitor; or hexadimethrine (both known antagonists of tissue plasminogen activator, Hageman factor, and serum kallikrein); or aprotinin (an antagonist of both plasmin and tissue kallikrein); or phenylmethanesulfonyl fluoride (a serine esterase (elastase) inhibitor); or pepstatin-A (an acid protease inhibitor which inactivates vascular permeability-inducing leukokinins). These data, together with the fact that VPF is produced and released into serum-free media, provides substantial evidence against it being one of the more commonly known serum-derived permeability mediators. Treatment with dithiothreitol inhibited VPF activity, indicating the presence of at least one essential disulfide bond in this molecule. Inhibition by dexamethasone of VPF expression in cultured malignant glial cells appears to be selective. Dexamethasone-induced inhibition of VPF was dose-responsive and was not associated with a parallel inhibition of cellular protein synthesis as determined by tritiated leucine incorporation into trichloroacetic acid-precipitable material. Inclusion of dexamethasone in the culture medium was not associated with altered cell viability or cell number. A series of in vivo studies confirmed the inhibition of VPF activity in test animals pretreated with dexamethasone. This steroid-induced inhibition was partially reversed by treatment of test animals with actinomycin D prior to exposure to dexamethasone.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Further characterization of malignant glioma-derived vascular permeability factor. 313 21

The balance of tissue-type plasminogen activator (t-PA) production and degradation determines its concentration in blood and tissues. Disturbance of this balance may result in either increased or decreased proteolysis. In the present study, we identified the receptor systems involved in the degradation of t-PA by human monocytes/macrophages in culture. Monocytes were cultured and became macrophages within 2 days. At 4 degrees C, 125I-t-PA bound to macrophages with high (apparent dissociation constant [kd], 1 to 5 nmol/L) and low affinity (kd > 350 nmol/L). At 37 degrees C, the cells internalized and degraded t-PA via the high affinity binding sites, which were partially inhibited by mannan. The low affinity binding sites were 6-aminohexanoic acid-inhibitable and not involved in t-PA degradation. Degradation of t-PA was upregulated during differentiation of monocytes to macrophages. Dexamethasone further upregulated the mannan-inhibitable t-PA degradation. Lipopolysaccharide downregulated both mannan-inhibitable and non-mannan-inhibitable t-PA degradation. Non-mannan-inhibitable degradation was completely blocked by recombinant 39-kD receptor-associated protein (RAP, inhibitor of lipoprotein receptor-related protein [LRP]), whereas mannan-inhibitable degradation was blocked by the addition of a monoclonal antibody against the mannose receptor. No differences between the degradation of t-PA and functionally inactivated t-PA were observed. We conclude that human monocyte-derived macrophages are able to bind, internalize, and degrade t-PA. Degradation of t-PA does not require complex formation with plasminogen activator inhibitors. The macrophages use two independently regulated receptors, namely, the mannose receptor and LRP, for the uptake and degradation of t-PA.
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PMID:Degradation of tissue-type plasminogen activator by human monocyte-derived macrophages is mediated by the mannose receptor and by the low-density lipoprotein receptor-related protein. 757 46

Blood fibrinolytic activity is mediated by plasma and cellular components. We have studied blood fibrinolytic activity in different species and investigated the distribution pattern in rats after modulation with PAF, dexamethasone, or retinoic acid. Whole blood and plasma activity were measured in an assay system using human or endogenous fibrin as substrate. When human fibrin was used as substrate marked species differences in distribution of fibrinolytic activity were observed. In rat and murine blood most fibrinolytic activity was associated with the plasma fraction (70% and 50% respectively) while in human and canine blood the plasma fraction contained only 30% of the blood fibrinolytic activity. When endogenous fibrin was used as substrate the distribution pattern of fibrinolytic activity in rat blood changed dramatically. Less than 25% of the blood fibrinolytic activity was now present in the plasma fraction. The fbrinolytic system was further investigated in rats using specific inhibitors of proteolytic activity. Blood fibrinolytic activity could be inhibited for 33% by antibodies raised against t-PA and 60% inhibition was obtained in the presence of amiloride. No significant effect of elastinal (an inhibitor of elastase) could be detected. Plasma fibrinolytic activity was not affected by these inhibitors. The fibrinolytic activity in plasma could be enhanced about 100-fold after i.v. PAF administration (10 micrograms/kg). This extra fibrinolytic activity could be fully blocked by antibodies raised against t-PA. Oral administration of dexamethasone or retinoic acid affected blood fibrinolytic activity by modulating selectively the activity mediated by the cellular fraction. Dexamethasone treatment (1 mg/kg) resulted in a 59% decrease of this fibrinolytic activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fibrinolytic activity in blood is distributed over a cellular and the plasma fraction which can be modulated separately. 774 Apr 59

The effect of oral administration of dexamethasone to rats on the haemostatic system was investigated. Dexamethasone was given once daily for 5 consecutive days. Plasma PAI-1 antigen levels were increased dose dependently (up to 210 +/- 29% of control values at a dose of 3 mg/kg) whereas no significant effects on plasma t-PA antigen levels were observed (131 +/- 6% compared with control values). In addition, treatment with 1 mg/kg dexamethasone decreased t-PA activity in tissue extracts of the aorta, heart and liver (65%, 28% and 58%, respectively) whereas tissue u-PA activity was not influenced. In vivo fibrinolytic activity was significantly decreased after dexamethasone treatment at a dose of 3 mg/kg but not at a dose of 1 mg/kg. The effect of dexamethasone on in vivo platelet aggregation was studied in an arterial thrombosis model. Dexamethasone treatment resulted in a two-fold decrease in arterial thrombosis at a dose of 0.1 mg/kg. At a dose of 1 mg/kg a less pronounced but significant decrease was observed. We conclude that in haemostasis the primary effect of dexamethasone treatment is an inhibition of arterial thrombosis by inhibition of platelet aggregation which is neutralized at higher doses by a decreased fibrinolytic activity.
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PMID:Dexamethasone affects platelet aggregation and fibrinolytic activity in rats at different doses which is reflected by their effect on arterial thrombosis. 805 58

We have performed a comparative study on tPA and PAI-1 mRNA expression in primary cultures of rat hepatocytes and elucidated the possible regulation of these factors by certain hormonal stimulation. The tPA mRNA increased 2- to 4-fold in the presence of cholera toxin (CT), dibutyryl cyclic AMP (dbcAMP), or 3-isobutyl-1-methyl xanthine (IBMX), but slightly decreased in the presence of dexamethasone. The tPA activity was also changed by these agents in a similar fashion. On the contrary, PAI-1 mRNA decreased with CT, dbcAMP, or IBMX, but increased transiently with dexamethasone. From results obtained with cycloheximide, ongoing protein synthesis was judged to be required for both PAI-1 induction with dexamethasone and PAI-1 suppression with IBMX, but not for the tPA induction with IBMX. Dexamethasone exerted opposite regulatory effects on the tPA mRNA expression depending on its concentration: at 10(-8) to 10(-6) M, it suppressed the expression; whereas at 10(-10) M, it elevated the expression.
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PMID:Regulation of tissue-type plasminogen activator (tPA) and type-1 plasminogen activator inhibitor (PAI-1) gene expression in rat hepatocytes in primary culture. 956 9


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