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)

Low-fat, high-fiber diets may influence the variables of blood coagulation and fibrinolysis associated with cardiovascular morbidity. Dietary fat content has been suggested as the important determinant. This hypothesis was tested in a strictly controlled dietary study of 13 healthy individuals. They were fed two experimental diets in a 2 x 2-week crossover trial. The diets differed in fat content (39% versus 31% of total energy), whereas the fatty acid composition and the fiber content were virtually identical. We observed no significant differences between diets in terms of fasting plasma levels of factor VII coagulant activity, fibrinogen, euglobulin fibrinolytic activity, tissue-type plasminogen activator (t-PA) activity, t-PA antigen, plasminogen activator inhibitor type 1 (PAI-1) antigen, or PAI activity. Serum levels of total cholesterol, high density lipoprotein cholesterol, and triglycerides were also unaffected. In conclusion, a moderate reduction in dietary fat intake, at a fixed fatty acid composition and dietary fiber intake, did not significantly influence blood coagulation, fibrinolysis, or blood lipids in the fasting state.
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PMID:Fasting blood coagulation and fibrinolysis of young adults unchanged by reduction in dietary fat content. 154 94

The effect of heart rate on plasma fibrinolytic activity was investigated in nine patients with dual chamber cardiac pacemakers before and after 10 min of stimulated tachycardia to 123 beats/min. The results were compared to seven volunteers who performed submaximal exercise to 90% target heart rate and to five of the seven who underwent a second period of exercise to a heart rate of 120 beats/min. During submaximal exercise (mean heart rate 152 beats/min) the median ECLT fell from 248 min (interquartile range 147.5-305) to 90 (55-202) P less than 0.01 and t-PA:Ag increased from 6.1 ng/ml (3.92-7.95) to 9.3 (8.45-12.7), P less than 0.025. PAI and PAI-1:Ag fell from 12.0 IU/ml (5.85-15.5) to 4.1 (1.85-11.67), P less than 0.01, and 9.7 ng/ml (2.8-10.6) to 6.7 (2.1-9.9), P less than 0.01 respectively. A lower level of exercise to 120 beats/min resulted in a reduction in ECLT from 215 min (167.5-228.5) to 135 (116-154), P = 0.05 and an increase in t-PA:Ag from 4 ng/ml (3.07-4.45) to 5.0 (3.3-5.22) P less than 0.05. PAI and PAI-1:Ag fell from 7.6 IU/ml (3.27-8.5) to 7.1 (2.77-7.4) and from 7.7 ng/ml (6.0-7.92) to 6.4 (4.8-7.3) respectively but these changes were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of exercise and heart rate on fibrinolytic activity. 832 78

The plasminogen activator (PA) activity in various cell lines is suppressed by glucocorticoids. These phenomena are attributed to either a suppression of PA biosynthesis, to an increase of PA inhibitor or to a combination of both. The regulation of urokinase (UK) production in a human pre-B cell lymphoma line, RC-K8, by dexamethasone (Dex) and phorbol myristate acetate (PMA) was investigated. RC-K8 is a cell line which is consistently producing a high molecular weight UK in the conditioned medium (Kubonishi, I., et al: Jpn. J. Cancer Res. 76, 12-15, 1985). The cells were cultured in RPMI-1640 with Dex or PMA for 1-4 days. UK activity was measured using a chromogenic substrate S-2444 and the antigen by an ELISA kit. PAI-1 and PAI-2 antigens were also measured by ELISA kits and the complex between PA and PAI was examined by SDS-PAGE fibrin-zymography. The UK secretion in RC-K8 cells was inhibited by cycloheximide and actinomycin D. PMA at 0.16-1.6 uM up-regulated the UK activity approximately two-fold, parallel with the antigen, whereas Dex at 1-10 uM decreased the UK expression approximately half. These were verified by SDS-PAGE fibrin-zymography. Neither PAI-1, PAI-2 nor PA/PAI complex was detected in the conditioned medium and in the cell lysate. These data suggest that PMA up-regulates the UK secretion without inducing PAIs and the down-regulation of the UK secretion by Dex results from the inhibition of the expression of UK itself but not from the induction of PAIs.
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PMID:Down-regulation of urokinase secretion from a human lymphoma cell line RC-K8 by dexamethasone without inducing plasminogen activator inhibitors. 163 98

Despite a clinical prophylactic efficacy of low molecular weight heparins (LMWHs) for 24 hrs after a single subcutaneous administration, the routine laboratory tests (anti-Xa, anti-IIa, Heptest, APTT which show a reliable in vitro dose-response) exhibit no ex vivo response after 6 hours. In addition, the values obtained in these assays do not correlate with clinical efficacy or bleeding side effects. With therapeutic doses of LMWHs, a proportionately higher effect was noted in these tests including, in addition, thrombin generation, Heptest-Hi, and thrombin time assays. However, the relevance of these assays to the clinical efficacy/toxicity of LMWHs remains unclear since they do not relate to the total pharmacodynamic effect. For example, protamine neutralization, adjunct drug treatment and a patient's own predisposing factors which contribute to the hemostatic balance may not be reflected in these assays. These observations point to the limitations of the available laboratory tests for monitoring LMWHs. In order to find a more sensitive means to detect the effects of LMWH, assays for specific molecular markers of coagulation and fibrinolysis activation were evaluated. Alterations in the levels of thrombin-antithrombin complex, t-PA, total degradation products and D-dimer assays were observed over a 7-10 day LMWH treatment period. Prothrombin fragment F1+2, modified antithrombin, PAI and fibrinogen degradation products were not significantly effected. The association of the changes observed in these markers to the mechanism of action of LMWH or to the efficacy of the treatment, however, remains to be determined.
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PMID:Laboratory monitoring of the clinical effects of low molecular weight heparins. 165 70

16 coagulant and 7 fibrinolytic parameters were determined in 121 normal subjects and 456 patients with various types of viral hepatitis. The results showed that plasma concentration of F VIII: c, vWF: Ag and vWF: Ag/VIII: c (P less than 0.01) were much higher than those in the controls. Plasma level of other coagulant factors was progressively reduced when the severity of hepatitis was decreased. The changes of fibrinolytic activity suggest that t-PA, PL and FDP were increased, while PAI, PLG, and alpha-PI were decreased. The results of this study may provide an experimental basis for further study of hemorrhage mechanism and prognosis in patients with viral hepatitis.
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PMID:[Changes in plasma coagulant factors and plasma fibrinolytic activity in patients with viral hepatitis]. 166 71

Serine protease inhibitors ("serpins") are highly homologous proteins which inhibit selected "target" serine proteases by acting as a pseudo-substrate. Their specificity is primarily determined by the amino acid sequence around the carboxyl-terminally located reactive center (P1-P1'). In addition, the association rate constant between a serpin and a serine protease can be dramatically increased by non-protein cofactors, such as heparin in the case of thrombin inhibition by antithrombin III. In an attempt to alter the specificity of PAI-1 from an inhibitor of the fibrinolytic system to an inhibitor of coagulation, we replaced P1-P1' or P3 through P3' of the reactive center of PAI-1 by the corresponding residues of antithrombin III and assessed whether the mutant proteins, purified from lysates of transformed Escherichia coli cells, had acquired thrombin inhibitory properties. The experiments were performed in the presence and absence of vitronectin, a multifunctional protein which has been shown to bind PAI-1 in plasma and in the matrix of endothelial cells. The second-order rate constants for t-PA inhibition of "wild-type" PAI-1 and PAI P1-P1'ATIII, irrespective of the presence of vitronectin, were similar, whereas replacing P3-P3' resulted in a 40-fold decrease of the second-order rate constant towards t-PA, again independent of vitronectin. In the absence of vitronectin, reactivity of PAI-1 and its "antithrombin III-like" variants towards thrombin was slow; however, PAI-1 P3-P3' ATIII had a 10-fold higher k1 than wild-type PAI-1 (1.3 x 10(4) M-1 s-1 versus 1.1 x 10(3) M-1 s-1). In contrast, in the presence of vitronectin, PAI-1 and even more rapidly PAI-1 P3-P3'ATIII were found to be effective thrombin inhibitors, with k1 values of 2.2 x 10(5) M-1s-1 and 1.8 x 10(6) M-1 s-1, respectively. Thus, in the presence of vitronectin, PAI-1 P3-P3'ATIII displays a 3-fold higher k1 with thrombin than with t-PA. It is shown that vitronectin enhances, in a dose-dependent manner, the formation of sodium dodecyl sulfate-resistant complexes between PAI-1 or mutants thereof and thrombin. Therefore, vitronectin is the first protein described to function as a cofactor for serpin specificity. PAI-1 is proposed to be a versatile inhibitor which, in the presence of vitronectin, can modulate both coagulation and fibrinolysis.
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PMID:Alteration of serpin specificity by a protein cofactor. Vitronectin endows plasminogen activator inhibitor 1 with thrombin inhibitory properties. 169

Several investigators have reported that tumor necrosis factor (TNF) can alter the production of plasminogen activator type-1 (PAI-1) and plasminogen activators (PAs) by endothelial cells in vitro. We have examined the in vivo effects of recombinant human TNF administration on fibrinolysis as assessed by parameters in plasma during a 24-hour period of continuous TNF infusion to 17 cancer patients with active disease. The plasma levels of PAI activity increased sevenfold after 3 and 24 hours of TNF infusion. This was the result of an increase of PAI-1 antigen; PAI-2 antigen was not detectable. Plasma concentrations of tissue-type PA (t-PA) antigen increased twofold to fivefold after 3 and 24 hours of TNF infusion, whereas urokinase-type PA antigen levels in plasma remained unaltered. After 3 hours of TNF infusion the plasma levels of alpha 2-antiplasmin were slightly decreased, 5% on average, suggesting that fibrinolysis continued. After 24 hours of TNF infusion a highly significant increase in fibrin- plus fibrinogen-degradation products, and separately of fibrin degradation products and fibrinogen degradation products, was found. This indicates that fibrinolysis persisted, at least partly, in the presence of high levels of PAI activity. Whereas PAI-1 production increased, t-PA production by human endothelial cells in vitro remains unaltered or even decreases on TNF addition. It has been shown previously that TNF infusion in our patients results in thrombin and fibrin generation. Therefore, it is possible that thrombin, not TNF, is the actual stimulus for t-PA production in our patients. We speculate that fibrin is formed during TNF infusions and that plasmin is generated by t-PA action immediately on the initial formation of (soluble) fibrin molecules. Such a process may explain the generation of degradation products of both fibrin and fibrinogen during infusion of TNF in patients.
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PMID:Progress of fibrinolysis during tumor necrosis factor infusions in humans. Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products. 170 65

Regulation of plasminogen activation is a key process in controlling proteolytic events in the extracellular matrix (ECM) and this regulation is achieved through the action of specific plasminogen activator (PA) inhibitors (PAIs). Type I PAI (PAI-1) is the physiological inhibitor both of urinary-type PA (u-PA) and tissue-type PA (t-PA) (Loskutoff et al., 1989) and is a major component of the ECM of cultured cells. This inhibitor may protect ECM constituents against cellular proteases and thus influence the cell migration and tissue destruction that occurs during development, inflammation and tumor metastasis. In this review, we discuss the properties of PAI-1 and the evidence that the binding of PAI-1 to ECM is mediated by serum-derived vitronectin (Vn).
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PMID:Interactions between type 1 plasminogen activator inhibitor, extracellular matrix and vitronectin. 171 15

The effects of metformin on the fibrinolytic system were studied pre- and post-venous occlusion in 38 Type 2 diabetic patients in a double-blind, placebo-controlled trial. After a 3-week run-in period, 21 patients received metformin and 17 placebo, for 6 weeks. In the metformin-treated patients basal plasminogen activator inhibitor-1 antigen (PAI-1Ag) fell from 57.4 micrograms l-1 before treatment to 36.1 (p less than 0.05) and 41.0 micrograms l-1 (p less than 0.01) after 3 and 6 weeks therapy. In this group post-venous occlusion PAI-1Ag also fell after 3 weeks (p less than 0.002) and 6 weeks (p less than 0.05) treatment. There were no changes in either basal or post-venous occlusion concentrations of PAI-1Ag in the placebo treated group. The fall in PAI-1Ag was not associated with an increase in basal plasminogen activator activity (PAA) which remained unchanged in both groups. Post-venous occlusion values for PAA in the metformin treated patients were increased at 3 weeks (p less than 0.05) although there was no difference at 6 weeks.
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PMID:Metformin causes a reduction in basal and post-venous occlusion plasminogen activator inhibitor-1 in type 2 diabetic patients. 171 32

The human U373 glioblastoma/astrocytoma cell line was found to constitutively produce and secrete a plasminogen activator and a plasminogen activator inhibitor. The plasminogen activator was identified as urokinase based on apparent molecular weight, immunoblotting with anti-urokinase antibodies, and Northern blotting with a human urokinase cDNA probe. The inhibitor secreted by U373 cells was found to be related to the PAI-1 molecule based on reactivity with anti-human PAI-1 antibodies, apparent molecular weight, and Northern blot analysis with a human PAI-1 cDNA probe. The expression of both urokinase and the PAI-1-like molecule by U373 cells could be modulated by phorbol myristate acetate or by inflammatory mediators such as interferon-gamma and interleukin-1. In the case of interleukin-1, the alpha form exhibited no detectable effect while the beta form not only elevated inhibitor levels, it also appeared to induce the production of tissue plasminogen activator. Thus, in these cells interleukin-1 beta induces alterations in PA and PAI expression and interleukin-1 alpha does not, even though the two forms are reported to utilize the same cellular receptor.
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PMID:Modulation of plasminogen activator and plasminogen activator inhibitor expression in the human U373 glioblastoma/astrocytoma cell line by inflammatory mediators. 172 61


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