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 effects of both clot-bound and circulating plasminogen activator inhibitor-1 (PAI-1) on endogenous fibrinolysis were investigated in a rat model of pulmonary embolism. Iodine-125 fibrin(ogen)-labeled blood-clot homogenates were delivered through the left jugular vein to the lung microvasculature, and the subsequent extent of the clot lysis was monitored by measuring the release of 125I-fibrin degradation products (FDPs) into the blood. Clots that had incorporated activated PAI-1 ex vivo were subsequently protected from dissolution in vivo in a dose-responsive manner (half-maximal concentration [IC50] = 4.3 micrograms/ml). PAI-1-containing clots also resisted lysis, as measured by the release of the specific FDP D-dimer. Plasma levels of plasminogen activator (PA) and PAI activity were unaltered by administration of PAI-1-containing clots, and the clot-protective effects of clot-bound PAI-1 were reversed by exogenous tissue-type plasminogen activator administration. Clot lysis was also inhibited in a dose-responsive manner (IC50 = 58 micrograms/kg) by intravenous bolus delivery of activated PAI-1 to the circulation. The clot-protective effects of circulating PAI-1 were correlated with dose-dependent increases in plasma PAI-1 antigen and activity levels and decreases in plasma PA levels (IC50 = 37 micrograms/ml). There was no evidence of any accumulation of circulating PAI-1 in the lungs. Latent PAI-1, whether delivered with or delivered after the clot homogenates, did not affect the clot-lytic process. Activated and latent PAI-1 was cleared from the circulation in a monophasic manner, with a half-life of approximately 32 and 7 minutes, respectively. The results indicate that both clot-bound and circulating PAI-1 are potent inhibitors of fibrinolysis in vivo. Clot-bound PAI-1 may inhibit PAs in the immediate vicinity of the clots, whereas circulating PAI-1 may act systemically by controlling overall levels of PAs present in the blood.
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PMID:Both circulating and clot-bound plasminogen activator inhibitor-1 inhibit endogenous fibrinolysis in the rat. 191 13

Defibrotide is a polydeoxyribonucleotide drug known to modulate the endothelial cell release of t-PA, PAI, and PGI-2 and to improve blood flow and perfusion. A double-blind, multicenter, placebo-controlled, dose comparison study was carried out to test the long-term efficacy and safety of defibrotide in patients with PAD (Leriche stage 2). Informed patients suffering from PAD were enrolled, and after a 15-day washout period were randomly allocated in a double-blind fashion to one of the three following treatments: defibrotide 400 mg (1 cps) b.i.d. for 6 months, defibrotide 400 mg o.d., or placebo. Absolute walking distance (AWD, treadmill) and ankle-arm pressure ratio (Winsor Index, WI) were evaluated at the beginning and after 30, 90, and 180 days after therapy. Two hundred twenty seven patients were recruited and 193 patients were included in the final analysis (800 mg: 67; 400 mg: 60; placebo: 66). All treatments brought about an increase in AWD placebo = +17%; 400 mg = +47%, 800 mg = +52%); however, patients treated with defibrotide exhibited a significantly better AWD at the end of treatment in comparison with placebo (p less than 0.01). AWD was not significantly different in the 400-mg and 800-mg groups. There was a trend indicating a possible improvement of WI after defibrotide, with higher WI in 800-mg patients in comparison with placebo (p less than 0.05). However, this difference was partly due to a decrease in arterial blood pressure elicited by the drug. The tolerability in all groups was optimal. These results indicate that orally administered defibrotide exerts symtomatic benefit in PAD patients and daily doses of 400 or 800 mg seem to be equivalent.
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PMID:A double-blind, multicenter, placebo-controlled, dose comparison study of orally administered defibrotide: preliminary results in patients with peripheral arterial disease. 194 94

The incidence of myocardial infarction and sudden cardiac death is highest in the morning. Inhibition of fibrinolytic activity in blood also peaks in the morning and this inhibition may favor the development of arterial thrombosis. It has been reported that patients treated with beta blockers do not show the typical circadian pattern of onset of myocardial infarction and sudden cardiac death. This study was undertaken to investigate whether beta blockade alters the circadian rhythm of 2 major fibrinolytic factors, tissue-plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Repeated blood samples were taken over a 24-hour period in 13 healthy volunteers: 7 taking 160 mg/day of long-acting propranolol orally for 14 days, and the other 6 taking no medications. Blood samples were analyzed for the plasma levels of t-PA activity, t-PA antigen, PAI activity and PAI-1 antigen. A significant circadian variation of all 4 parameters was present in both groups. No significant differences in peak and nadir values, 24-hour mean, amplitude of fluctuation, and time of peak and nadir were found between the treated and untreated subjects. The data therefore suggest that propranolol treatment does not affect the plasma concentrations at rest or the endogenous circadian rhythm of t-PA and PAI-1 in healthy volunteers. The reported alteration in the circadian pattern of onset of myocardial infarction and sudden cardiac death by beta blockers does not appear to be mediated by effects on the fibrinolytic system.
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PMID:Effect of propranolol (long-acting) on the circadian fluctuation of tissue-plasminogen activator and plasminogen activator inhibitor-1. 195 Nov 15

Plasminogen activator inhibitor (PAI-I) rapidly inactivates tissue plasminogen activator (t-PA) and urokinase (UK) with nearly identical association rate constants. The contributions of Ser344, Ala345, and Arg346 (P3, P2, and P1 residues, respectively) in PAI-I to inhibition of UK and t-PA were evaluated using combinatorial mutagenesis of the human PAI-I cDNA. A bacteriophage lambda expression library potentially encoding the 8000 unique PAI-I species were screened for inhibitory activity against UK using a fibrin indicator gel. 390 plaques demarcated by zones of retarded fibrinolysis were analyzed to determine the DNA sequences of their associated active PAI-1 species. We found 134 unique PAI-1 variants that retained inhibitory activity towards UK; they contained a variety of amino acids in their P3 and P2 positions but only Arg or, infrequently, Lys in their P1 position. Each of the unique active PAI-1 were assayed for inhibitory activity towards UK or t-PA; many substitutions differentially affected the ability of the inhibitor to inactivate UK and t-PA. For example, replacement of Ser344 and Ala344 with Val and Pro, respectively, yielded a PAI-1 variant exhibiting an association rate constant that was unchanged for t-PA but decreased 23-fold for UK, relative to native PAI-1. In general, the PAI-1 variants were more potent inhibitors of t-PA than UK. Hence, t-PA appears more tolerant than UK of structural diversity present in the P3 and P2 positions of the PAI-1 variants.
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PMID:Combinatorial mutagenesis of the reactive site region in plasminogen activator inhibitor I. 202 63

Interaction between endothelial cells (EC) and platelets in culture was shown to regulate the fibrinolytic system of the aortic EC. Untreated porcine EC from aorta exhibited almost no net fibrinolytic activity and zymographic assay have shown a single fibrin lysis band of 105 kDa corresponding to a tPA-PAI complex. Incubation of aortic EC with intact platelets stimulated a cell-associated fibrinolytic activity of the urokinase type as evidenced by a plasminogen-dependent fibrin independent amidolytic activity, and the appearance of a new 48 kDa lysis band on zymography. However, in the culture medium of platelet-treated aortic EC, a new lysis band of 92 kDa appeared with no associated amidolytic activity suggesting that the 48 kDa plasminogen activator secreted by the aortic EC after treatment with platelets is complexed to the inhibitor PAI1. This modulation of fibrinolytic activity depends on the EC origin since it is not observed with pulmonary artery EC, and represents a new concept in fibrinolysis regulation by cell-cell interaction.
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PMID:Modulation of endothelial cells fibrinolytic activity by platelets. 202 42

Levels of major parameters of fibrinolysis were measured in 50 normal human fetuses between 19 and 39 weeks of gestation and compared to those of 50 healthy normal pregnant women and 30 adult controls. In fetuses, euglobulin clot lysis time (ECLT) was significantly shortened, plasminogen level was low and histidine-rich glycoprotein undetectable. While t-PA and u-PA levels were slightly lower than in adult controls, a significant decrease in PAI activity was demonstrated and no PAI-2 could be detected in fetal plasma. In contrast with these findings, the fibrinolytic equilibrium of pregnant women exhibited a prolonged ECLT and a strong increase in both PAI activity and PAI-2 antigen levels, while only a moderate elevation in u-PA and t-PA levels was measured.
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PMID:Comparative study of the fibrinolytic system in human fetuses and in pregnant women. 202 51

Defibrotide is a polydeoxyribonucleotide salt that shows antithrombotic activity through a suggested profibrinolytic mechanism. To study the effectiveness of defibrotide in atherosclerosis, we evaluated the fibrinolytic and coagulation behavior in normal subjects and patients with atherosclerotic disease, before and after single or repeated intravenous defibrotide infusion. A significant shortening of the ELT was found in all subjects. However, since neither t-PA increase nor PAI decrease was observed, we suggest that the profibrinolytic response to defibrotide may be due to mechanisms other than t-PA stimulation. Our results provide further evidence for the usefulness of defibrotide antithrombotic prophylaxis in atherosclerosis.
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PMID:Fibrinolytic effects of defibrotide in atherosclerotic patients. 206 62

Twenty outpatients presenting with Raynaud's phenomenon secondary to clinical or preclinical inflammation of connective tissue were treated orally with defibrotide 400 mg three times daily or a matching placebo in a randomized double-blind study. The test product defibrotide (a polydeoxyribonucleic acid compound of animal origin with demonstrated profibrinolytic activity when administered parenterally) was administered orally for 3 weeks in order to explore its effects on the parameters of extrinsic fibrinolysis before and after venous stasis. The antigen of t-PA and its inhibitor PAI, free and total, and the biologic activity of PAI were assayed in basal conditions and after treatment. Although a marked increase of t-PA was seen with the active treatment, PAI activity was significantly reduced by defibrotide. Immunoreactive PAI was not significantly modified by treatment, even though it dropped considerably after venous stasis in the defibrotide group. Thus, the disturbance of endothelial function that seems to occur in vasculitis and in Raynaud's phenomenon secondary to inflammation of connective tissue (or so suspected to be) would constitute the basis of a disturbance of fibrinolysis, which oral defibrotide seems able to correct. Further studies are warranted to define the clinical effectiveness of this treatment in patients with Raynaud's phenomenon.
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PMID:Deficient fibrinolytic response in patients with Raynaud's phenomenon and its correction with defibrotide. 206 63

Defibrotide, a deoxypolyribonuclide, has been found to modulate endothelial cell function causing increase in t-PA and decrease in PAI levels and also increase in PGI2 production. In addition, it increases platelet c-AMP levels and decreases MDA and TXB2 formation in human. Defibrotide inhibits platelet aggregate formation in vitro experiments as well as end-to-end anostomosis in rats. So, defibrotide inhibits the activation of platelets. Besides an increase of protein C and S levels a synergic action of heparin was observed in animal experiments. A strong antithrombotic effect has been observed in animal models. The drug has a beneficial effect in the cases of DVT, POVD, stroke and thromboembolism. Through its action we may say that the drug acts in a novel fashion in contrast to the other drugs used in this area. Defibrotide is a single-stranded polydeoxyribonucleotide obtained from deoxyribonucleic acid of mammalian lungs by controlled depolimerization. Since 1981 in our laboratory and in the clinical department we have been investigating a newly developed agent defibrotide in vitro experiments, animal experiments, and also its clinical pharmacology and clinical application. Some of our findings are already published and compared with literature (40, 43, 46). Because of the limited space we are not going to review the literature in detail but we are going to summarize our observations on this compound in the following order. I--in vitro experiments, II--Animal experiments, III--clinical pharmacology in human.
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PMID:The pharmacology and clinical pharmacology of defibrotide: a new profibrinolytic, antithrombotic and anti-platelet substance. 210 24

Several groups have demonstrated that radioiodinated tissue-type plasminogen activator (t-PA) binds to saturable sites on human umbilical vein endothelial cells (HUVECs) in culture (Hajjar, K. A., Hamel, N. M., Harpel, P. C., and Nachman, R. L. (1987) J. Clin. Invest. 80, 1712-1719; Beebe, D. P. (1987) Thromb. Res. 46, 241-254; Barnathan, E. S., Kuo, A., van der Keyl, H., McCrae, K. R., Larsen, G. L., and Cines, D. B. (1988) J. Biol. Chem. 263, 7792-7799). Here we report that most of the specific binding of 125I-t-PA to our HUVEC cultures is accounted for by binding to (i) plasminogen activator inhibitor type 1 (PAI-1), a t-PA inhibitor produced in abundance by HUVECs; and (ii) specific binding sites present on the plastic culture surface. The contribution of the sites on plastic can be eliminated by taking several precautions. Then, most or all of the specifically bound 125I-t-PA is present in a sodium dodecyl sulfate-stable 110-kDa 125I-t-PA.PAI-1 complex. Interestingly, a radioiodinated mutant form of t-PA, S478A, which is catalytically inactive and therefore unable to form the covalent complex with PAI-1, still binds to HUVECs. In fact, this ligand binds to HUVECs in 10-30-fold greater amounts than does wild-type 125I-t-PA (resulting in greater than 1 x 10(7) S478A 125I-t-PA molecules bound/cell at 12 nM ligand concentration). In contrast, diisopropyl fluorophosphate-treated t-PA binds to HUVECs in much smaller amounts than does wild-type t-PA. Several findings suggest that PAI-1 is a major binding site for S478A t-PA. The vast amount of binding observed with S478A t-PA, compared with wild-type t-PA, may be accounted for by an observed large scale release of wild-type 125I-t-PA.PAI-1 complexes from the solid phase (cells or extracellular matrix) into the culture medium. Immunoprecipitation experiments demonstrate that, in contrast to wild-type t-PA, S478A t-PA does not extract [35S]methionine-PAI antigen from metabolically labeled extracellular matrix. It is proposed that t-PA releases PAI-1 from the solid phase when it forms the irreversible covalent complex with the inhibitor, a process that does not occur with the catalytically inactive mutant form of t-PA.
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PMID:Interaction of wild-type and catalytically inactive mutant forms of tissue-type plasminogen activator with human umbilical vein endothelial cell monolayers. 210 33


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