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)

The vascular endothelium plays an important role in fibrinolysis by producing tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI). The monokine tumor necrosis factor (human recombinant TNF) increased the production of PAI by cultured human endothelial cells from umbilical vein (twofold) and from foreskin microvessles (four to eight fold). This was demonstrated by titration of endothelial cell-conditioned medium with t-PA, by reverse fibrin autography, and by immunoprecipitation of [35S]PAI-1 by anti-PAI-1 IgG. TNF also induced a marked increase of PAI-1 messenger RNA (mRNA) in the cells. The stimulation of PAI activity by TNF was seen at 4 U/mL and reached a maximum at 500 U/mL. Human recombinant lymphotoxin and interleukin-1 (alpha and beta) also stimulated the production of PAI activity, while interleukin-6 was ineffective. Separate additions of TNF or interleukin-1 (IL-1) at optimal concentrations (500 U/mL and 5 U/mL, respectively) resulted in a comparable stimulation of PAI production by endothelial cells. The simultaneous addition of both mediators resulted in an additive effect. The effect of TNF could not be prevented by the addition of polymyxin B or by anti-IL-1 antibodies. Therefore, it is unlikely that TNF acts through the induction of IL-1 secretion by endothelial cells. Two hours after a bolus injection of 250,000 U/kg TNF into rats, a fivefold increase in circulating PAI levels was found. In the next ten hours, the levels returned to normal. Blood platelets do not significantly contribute to the increase in circulating PAI, because the number of platelets did not change after TNF injection and the amount of PAI in blood platelets is not sufficient for several hours during an increase in PAI activity. The acute phase reactants, fibrinogen and alpha 2-antiplasmin in rat plasma, were altered little if any two to 24 hours after injection of 250,000 U/kg TNF. In vitro, TNF did not change PAI production by human and rat hepatocytes in primary monolayer culture. Therefore, it is most likely that vascular endothelial cells contribute to the increased amount of circulating PAI induced by TNF in vivo. This increase in PAI activity might decrease fibrinolysis.
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PMID:Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo. 314 Sep 9

Alteration of the fibrinolytic system is considered to be important in the development of deep venous thrombosis (DVT). Using specific assays for tissue plasminogen activator (t-PA) activity, t-PA inhibitor (PAI) and t-PA antigen, we measured these activities in 16 women who developed DVT during their pregnancies. A group of 24 healthy females of comparable age was studied as controls. PAI was increased in 87% of these patients compared to the healthy controls. In some of these patients a defect in release of t-PA from vascular endothelium was found as well. The site at which blood was sampled for analysis appeared to be an important criterion in the ex vivo assessment of functional t-PA reserve and PAI levels, though relatively less so for the latter measurement. The unaffected lower limbs, relative to the unaffected upper limbs, showed an increase in PAI and a demonstrable decrease in t-PA release, both representing increased risk factors for rethrombosis. The affected lower limbs showed similar but more accentuated changes in these parameters.
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PMID:Altered fibrinolysis in DVT: influence of site of sampling. 314 91

The prolonged partial thromboplastin time observed in the plasma of a 36 year old asymptomatic man was related to the reduced prekallikrein activities (coagulant; antigenic; and amidolytic) and the absence of coagulant and immunologic activities of high molecular weight kininogen (HMWKg). The patient's plasma also exhibited impaired surface-mediated fibrinolysis and impaired generation of kallikrein. The coagulation defect was identified as the "Fitzgerald trait". The levels of CH50, C2, C4 and C-1 inactivator were normal. Venous occlusion in the patient gave rise to a normal release of extrinsic plasminogen activator from the vascular endothelium. The administration of DDAVP led to a FVIII/VWF response which was similar to that obtained in healthy subjects. No alteration could be observed in the contact phase proteins after DDAVP administration.
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PMID:New congenital deficiency of high molecular weight kininogen and prekallikrein (Fitzgerald trait). Study of response to DDAVP and venous occlusion. 363 67

Oral administration of clinical-type high molecular weight urokinase (HMW-UK) in a single dose of 30,000-60,000 International Units (IU) in enteric-coated capsules, in a group of normal human subjects, induced a plasma fibrinolytic state suggesting transport of HMW-UK across the intestinal tract. Other groups of human subjects were given a single dose of 120,000 IU daily of pure HMW-UK for 1 d and 7 d together with a placebo dose, all of the ingredients except urokinase (UK), daily for 7 d. UK-type proteins were isolated from the plasma of blood samples drawn 6 h after administration of the final dose, by a sequential two-step affinity chromatography method first with [N alpha-(epsilon-aminocaproyl)-DL-homoarginine hexylester]-Sepharose and second with a specific rabbit anti-HMW-UK-IgG-Sepharose. The yield of UK-type proteins from the 7-d group, 0.79 mg/dl, was approximately twofold greater than that obtained from either the placebo or 1-d groups. The specific plasminogen activator activity of the 1-d and 7-d groups were similar, 508 and 537 IU/mg protein, respectively; negligible plasminogen activator activity could be detected in the placebo group. The kinetics of activation parameters of human Glu-plasminogen of the UK-type protein, isolated from the 1-d group, were similar to those obtained with urinary HMW-UK. The UK-type proteins isolated only from the 7-d group showed, in sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis, a major protein band of molecular weight 53,000 in the same position as HMW-UK. In addition, two other major protein bands of approximately 140,000 and approximately 120,000 mol wt were found in the 7-d placebo-, and 1-d groups, and also in the 7-d group. The 53,000 mol wt protein, about 50% of the total protein in the 7-d group, was further purified by preparative SDS-polyacrylamide gel electrophoresis, and found to be a two-chain protein with a specific activity of 1,241 IU/mg protein. The protein showed common antigenic determinants with urinary HMW-UK. The oral administration of 120,000 IU HMW-UK to human subjects for 7 d stimulated the synthesis of a UK-type protein of 53,000 mol wt, probably the zymogen, from either the liver or vascular endothelium, which was released into the circulation, and converted into active UK by circulating plasmin. The induction of the fibrinolytic state produced the conversion of native circulating Glu-plasminogen into the degraded Lys-plasminogen form, which was found in large amounts in the plasma of the 7-d group. The new plasma components, e.g., the 53,000-mol wt UK-zymogen and Lys-plasminogen, could play an important role in clot resolution of the fibrin-thrombus in thromboembolic diseases. Oral administration of HMW-UK has been shown to be clinically effective in patients with cerebral thrombosis in a multicenter double blind study.
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PMID:Transport of urokinase across the intestinal tract of normal human subjects with stimulation of synthesis and/or release of urokinase-type proteins. 392 68

The distribution of plasminogen activator in fresh human prostatic tissue has been studied, using a histological technique. The vascular endothelium consistently showed fibrinolytic activity while inconstant and lesser activity arose from the epithelial cells of glands and ducts. Increased epithelial activity was often accompanied by evidence of trauma. Activity of the secretions was insignificant. The source of the fibrinolytic activity of blood in prostatic disease and of the seminal fluid remains uncertain, and cannot yet be ascribed to the prostatic epithelium.
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PMID:Plasminogen activator in the human prostate. 579 31

Increasing insight into the mechanism of thrombolysis has led to the development of highly effective thrombolytic agents. Further progress in thrombolytic therapy is expected by the use of extrinsic plasminogen activator from vascular endothelium and of temporarily blocked (acylated) fibrinolytic enzymes. Extensive studies on fibrinolytic/thrombolytic substances will lead to a new generation of activator of fibrinolysis that interferes with the biosynthesis and release of plasminogen activator. Such agents will be suited for treatment of hyperfibrinolytic states.
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PMID:[Pharmacological potentials for activating the fibrinolytic system]. 638 Jan 26

We have studied vessel wall function in two groups of patients with chronic renal failure - 1) conservative treatment only and 2) maintenance hemodialysis. Three proteins synthesized by vascular endothelium-plasminogen activator (PA), factor VIII related antigen (VIII:RAg) and antithrombin III (ATIII) - were assayed before and after a fifteen minute period of venous occlusion. The release of PA was significantly reduced in patients on maintenance hemodialysis as compared to both undialyzed uremics and controls. Lesser amounts of VIII:RAg were also released by hemodialysis patients than by undialyzed uremics. These defects, which are suggestive of vessel wall dysfunction on maintenance hemodialysis, may contribute to the high incidence of arteriopathy and thrombotic disease observed in this group of patients.
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PMID:Impaired vessel wall response to venous occlusion in patients with chronic renal failure on maintenance hemodialysis. 644 60

State of the anticoagulation system was studied after intravenous administration of trypsin at doses similar to the concentration of alpha-thrombin, activating chemoreceptors of vascular walls. Trypsin at doses 0.5 microM-3.7 microM did not affect the anticoagulation system as indicated by unaltered rate of nonenzymatic fibrinolysis. Occurrence of trypsin in blood led to generation of thrombin, which caused limited proteolysis of fibrinogen with subsequent increase in content of soluble fibrin, but did not stimulate the anticoagulation system. Distinct stimulation of the enzymatic fibrinolysis resulted from both liberation of plasmin due to direct proteolysis of plasminogen and unspecific release of the plasminogen activator after destruction of vascular endothelium. High doses of alpha-thrombin (70 NIH un per 1 ml of the preparation) did not activate the anticoagulation system but the total fibrinolytic activity was increased die to elevation in the ratio of enzymatic fibrinolytic activity. The data obtained suggest that the proteolytic activity of thrombin and trypsin is not responsible for the reflectory reaction of the anticoagulation system. High specificity of alpha-thrombin, caused by the presence in its structure of the recognizing sites of high molecular substrates, enables the enzyme to interact with chemoreceptors of vascular walls and to stimulate the anticoagulation system.
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PMID:[Enzymic and non-enzymic fibrinolysis during intravenous administration of trypsin]. 654 8

In diabetes mellitus the vascular endothelium often produces and releases abnormally low amounts of plasminogen activator, leading to an impaired fibrinolytic system, which might be of importance for the development of angiopathy. In this study tests of autonomic neuropathy (AN) were performed on diabetics without autonomic symptoms. It was discovered that diabetics without AN had a significantly lower mean fibrinolytic response to stimulation than nondiabetic controls, whereas this reduction was not found in those with AN. The suggestion that asymptomatic AN might induce a normalization of the impaired fibrinolytic system in diabetes, and thus have a modifying effect on the rate of development of angiopathy, requires further study to be properly evaluated.
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PMID:Fibrinolytic activity, autonomic neuropathy, and circulation in diabetes mellitus. 660 36

Des-amino-D-arginine vasopressin (DDAVP) stimulates the release of factor VIII and plasminogen activator from the vascular endothelium. An infusion of exogenous factor VIII given to haemophiliacs causes an increase in platelet activation. This activation does not occur after stimulating a rise in the patient's own factor VIII level caused by DDAVP infusion. We hypothesised therefore that DDAVP could also cause the endothelial release of prostacyclin (PGI2), a potent anti-platelet agent which would counteract the aggregating effect of factor VIII. To examine this possibility we studied the effect of DDAVP on prostacyclin release, as measured by its stable metabolite 6-oxo-PGF1 alpha, in vitro and in vivo. Rabbit aortic rings were incubated with different concentrations of DDAVP using saline as control. The supernatant was assayed for 6-oxo-PGF1 alpha by radioimmunoassay. All concentrations of DDAVP gave a significant release of 6-oxo-PGF1 alpha. Vasopressin was much less potent. When DDAVP was infused into haemophilic patients there was a significant increase in circulating 6-oxo-PGF1 alpha levels immediately after the infusion. The facial flushing observed as a side-effect of DDAVP could therefore be prostacyclin-mediated. We confirmed this by abolishing the DDAVP induced flushing seen in normal subjects by prior treatment with aspirin which inhibits PGI2 formation.
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PMID:DDAVP stimulates prostacyclin production. 680 93


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