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)

This study was undertaken to determine the role of platelet glycoprotein (GP) IIb/IIIa receptors in the modulation of plasminogen activator type-1 (PAI-1) release from human platelets as compared to other platelet functions. To address this issue, the effect of various agonists on human platelet aggregation, [125I]fibrinogen binding and the release of PAI-1 was examined in normal and Glanzmann's thrombasthenic (GT) platelets. In control subjects, maximum platelet aggregation and PAI-1 secretion were observed within 5 min in response to the different agonists including thrombin, collagen, adenosine diphosphate (ADP), and arachidonic acid. Agonist-induced platelet GpIIb/IIIa receptor activation was confirmed by [125I]fibrinogen binding analysis. In contrast, platelets from GT subjects demonstrated a lack of fibrinogen binding and a lack of an aggregatory response to all agonists tested except to the GPIb- mediated aggregation induced by ristocetin. However, GT platelets demonstrated normal responsiveness in secreting PAI-1 in response to the various agonists. Similarly, when platelet GpIIb/IIIa receptors were blocked in normal platelets by the tripeptide Arg-Gly-Asp (RGD) or the tetrapeptide Arg-Gly-Asp-Ser (RGDS) at 10(-3) M, agonist-induced platelet aggregation and fibrinogen binding were blocked, but platelet PAI-1 release was not blocked. Furthermore, flow cytometric analysis using dual fluorescence markers for the platelet GPIIb/IIIa membrane receptors (FITC-labeled cyclic RGD analog, XL086) and for the alpha granule (PE-monoclonal antibody for P-selectin) demonstrated a dissociation between the platelet GPIIb/IIIa receptors and granular secretion. These results suggest a lack of a role for platelet GpIIb/IIIa receptors in the modulation of platelet PAI-1 release.
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PMID:Role of platelet GpIIb/IIIa receptors in the modulation of platelet plasminogen activator inhibitors type-1 (PAI-1) release. 815 39

Unlike coronary thrombolysis, the role of platelet activity in the outcome of local thrombolytic therapy for peripheral ischaemia is not well understood. In the present study ten patients undergoing local pulse spray thrombolysis (PST) with recombinant tissue-type plasminogen activator (rt-PA), six patients undergoing conventional infusion thrombolysis (CT) with rt-PA and another six patients undergoing arteriography with iopamidol were studied. Venous blood samples obtained before and after the procedure were analysed using a flow cytometric technique for detection of platelet activation after labelling platelets with VH10, a monoclonal antibody against P-selectin. In the present study no significant differences were observed in P-selectin expression before and after any of the procedures, except that P-selectin expression following ADP stimulation was reduced in patients who had received conventional thrombolysis. Unexpectedly, we observed relatively greater P-selectin expression, particularly after ADP stimulation, both before and following thrombolysis in ten patients in whom thrombolysis was successful compared with six patients in whom thrombolysis was unsuccessful. ADP-induced P-selectin expression on platelets may therefore be a useful predictor of outcome of peripheral intra-arterial thrombolysis.
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PMID:ADP-induced P-selectin expression on platelets as a predictor of successful thrombolysis. 873 36

In previous studies we have shown that, after stimulation by a receptor ligand such as thrombin, tissue-type plasminogen activator (tPA) and von Willebrand factor (vWf) will be acutely released from human umbilical vein endothelial cells (HUVEC). However, the mechanisms involved in the secretion of these two proteins differ in some respects, suggesting that the two proteins may be stored in different secretory granules. By density gradient centrifugation of rat lung homogenates, a particle was identified that contained nearly all tPA activity and antigen. This particle had an average density of 1.11-1.12 g/ml, both in Nycodenz density gradients and in sucrose density gradients. A similar density distribution of tPA was found for a rat endothelial cell line and for HUVEC. After thrombin stimulation of HUVEC to induce tPA secretion, the amount of tPA present in high-density fractions decreased, concomitant with the release of tPA into the culture medium and a shift in the density distribution of P-selectin. vWf, known to be stored in Weibel-Palade bodies, showed an identical distribution to tPA in Nycodenz gradients. In contrast, the distribution in sucrose gradients of vWf from both rat and human lung was very different from that of tPA, suggesting that tPA and vWf were not present in the same particle. Using double-immunofluorescence staining of HUVEC, tPA- and vWf-containing particles showed a different distribution by confocal microscopy. The distribution of tPA also differed from the distribution of tissue factor pathway inhibitor, endothelin-1, and caveolin. By immunoelectronmicroscopy, immunoreactive tPA could be demonstrated in small vesicles morphologically different from the larger Weibel-Palade bodies. It is concluded that tPA in endothelial cells is stored in a not-previously-described, small and dense (d = 1.11-1.12 g/ml) vesicle, which is different from a Weibel-Palade body.
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PMID:An endothelial storage granule for tissue-type plasminogen activator. 931 43

The initial step in atherosclerosis is the rapid targeting of monocytes to the sites of inflammation and endothelial injury. Serum levels of intercellular adhesion molecule-1 were found to be increased in ischaemic heart disease patients and polymorphisms in the E-selectin gene were associated with accelerated atherosclerosis in young (age < 40 years) patients, further suggesting a role of inflammation in atherosclerosis. Cholesterol loading in macrophages was found to induce interleukin-8 expression, suggesting an association between foam cell formation and beta 2-integrin-dependent adhesion of leukocytes. Enhanced endothelium-platelet interaction induced by hypercholesterolaemia is mediated by von Willebrand factor, whereas platelet adhesion to subendothelial matrix is mediated by fibulin-fibrinogen complexes. Activated platelets mediate the homing of leukocytes by interaction with the subendothelial matrix under shear stresses that do not allow neutrophil adhesion. They may also contribute to the oxidative modification of LDL, provide a source of lipids for foam cell generation and contribute to smooth muscle cell proliferation. Oxidized LDL induces tissue factor in macrophages that also provide sites for fibrin polymerization and decreases the anticoagulant activity of endothelium by interfering with thrombomodulin expression and inactivating tissue factor pathway inhibitor. Intravascular fibrinolysis induced by tissue-type plasminogen activator or urokinase may contribute to the initiation of atherosclerosis by inducing P-selectin and platelet activating factor as well as to plaque rupture, either directly or indirectly, by activating metalloproteinases. Plasminogen activator inhibitor-1 inhibits smooth muscle cell migration and, in the presence of vitronectin, promotes the clearance of thrombin by LDL receptor-related protein at sites of endothelial injury.
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PMID:Thrombosis and atherosclerosis. 933 57

The mechanisms that underlie reocclusion during thrombolytic therapy have not yet been clarified. The purpose of this study was to investigate the activating effects of tissue-type plasminogen activator and urokinase and the inhibitory effects of acetylsalicylic acid by measuring platelet surface P-selectin as a marker of platelet activation. After addition of urokinase (final concentration 192 U/ml, 1920 U/ml, or 19,200 U/ml) or tissue-type plasminogen activator (final concentration 120 U/ml, 1200 U/ml, or 12,000 U/ml) to platelet-rich plasma from 12 healthy persons, platelet surface P-selectin expression was measured by means of flow cytometry with an anti-CD62 monoclonal antibody. The presence of urokinase and tissue-type plasminogen activator increased platelet surface P-selectin expression in a concentration-dependent manner. In the next step, either 160 mg/day (n = 6) or 660 mg/day (n = 6) acetylsalicylic acid was administered to the 12 healthy persons, and venous blood samples were collected after 7 days of treatment. Platelet surface P-selectin expression was measured with the method used earlier and after addition of tissue-type plasminogen activator or urokinase. Although the effect of acetylsalicylic acid at 160 mg/day on P-selectin expression was minimal, a dose of 660 mg/day suppressed platelet P-selectin expression and inhibited the platelet activating effects of tissue-type plasminogen activator and urokinase in a statistically significant way. Platelets were activated by tissue-type plasminogen activator or urokinase, and this platelet activation was suppressed with administration of acetylsalicylic acid at 660 mg/day.
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PMID:Human platelet activation by thrombolytic agents: effects of tissue-type plasminogen activator and urokinase on platelet surface P-selectin expression. 948 75

P-selectin is translocated from platelets and endothelial cells to initiate the first step in a sequence of events leading to the adherence of leukocytes, possibly inducing reperfusion injury and the no-reflow phenomenon in acute myocardial infarction (AMI). This study was undertaken to investigate plasma P-selectin in AMI patients undergoing coronary recanalization therapy. A total of 40 patients were studied: 20 patients with AMI who underwent coronary recanalization by direct percutaneous transluminal coronary angioplasty (PTCA), 10 patients with AMI who underwent thrombolytic therapy by tissue-type plasminogen activator (TPA), and 10 patients with stable angina pectoris who underwent elective PTCA. Blood samples were obtained from systemic arteries before and immediately after PTCA or thrombolytic therapy. Plasma-soluble P-selectin was measured by enzyme immunoassay. Plasma P-selectin was significantly higher in AMI than in stable angina pectoris (176.6 +/- 12.9 ng/mL vs 91.4 +/- 9.5 ng/mL, p<0.001). Plasma P-selectin did not change significantly as a result of elective PTCA in patients with stable angina (from 91.4 +/- 9.5 ng/mL to 87.9 +/- 7.9 ng/mL). Plasma P-selectin was decreased by direct PTCA in all of the 20 patients with AMI (from 176.2 +/- 17.7 ng/mL to 141.7 +/- 12.6 ng/mL; p<0.001, paired t-test), whereas it was increased by thrombolysis using TPA in nine of the 10 AMI patients (from 177.4 +/- 17.2 ng/mL to 248.8 +/- 17.3 ng/mL, p<0.005). Increased P-selectin activity in AMI appeared to be attenuated by direct PTCA, but augmented by thrombolysis, possibly due to direct stimulatory effects of TPA on P-selectin expression. This may lead to less favorable results in salvaging the ischemic myocardium by thrombolytic than mechanical coronary recanalization therapy in AMI.
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PMID:Plasma soluble P-selectin in acute myocardial infarction: effects of coronary recanalization therapy. 978 45

The blockade of the platelet integrin glycoprotein (GP) IIb/IIIa has proved to be an effective antiplatelet therapy. Profound thrombocytopenia has repeatedly been described as an adverse effect in patients treated with GP IIb/IIIa inhibitors, but its mechanism has not been elucidated yet. With use of flow cytometry, the activation status of platelets was monitored in 26 patients presenting with acute myocardial infarction who were treated with the GP IIb/IIIa inhibitor abciximab alone or in combination with the fibrinolytic agent reteplase. Fibrinogen and PAC-1 (a GP IIb/IIIa activation-specific monoclonal antibody) binding, as well as P-selectin expression on unstimulated platelets were constant in 25 patients throughout a follow-up of 7 days. In 1 patient (D.F.), the percentage of platelet-binding fibrinogen increased from 2.2% to 17.8%, for PAC-1 from 2.8% to 13.2%, and for P-selectin expression from 10.2% to 58.3% 10 minutes after the start of treatment. Furthermore, D.F. had a decrease in single platelet count in ethylenediaminetetraacetic acid-, citrate-, and heparin-anticoagulated and native blood. Blood films revealed platelet aggregates. In vitro testing of D.F.'s blood 2 and 4 weeks after initial admission demonstrated a reinduction of fibrinogen and PAC-1 binding to platelets, an increase of P-selectin expression, and formation of platelet aggregates following exposition of platelets to abciximab in vitro. In summary, this report describes the induction of platelet activation by a GP IIb/IIIa inhibitor in vivo and reinduction in vitro in direct association with thrombocytopenia. Platelet activation by GP IIb/IIIa inhibitors may be one potential mechanism for GP IIb/IIIa inhibitor-induced thrombocytopenia.
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PMID:Platelet activation as a potential mechanism of GP IIb/IIIa inhibitor-induced thrombocytopenia. 1048 48

The stimulation of regulated exocytosis in vascular endothelial cells (EC) by a variety of naturally occurring agonists contributes to the interrelated processes of inflammation, thrombosis, and fibrinolysis. The Weibel-Palade body (WPB) is a well-described secretory granule in EC that contains both von Willebrand factor (vWF) and P-selectin, but the mechanisms responsible for the targeting of these proteins into this organelle remain poorly understood. Through adenoviral transduction, we have expressed human growth hormone (GH) as a model of regulated secretory protein sorting in EC. Immunofluorescence microscopy of EC infected with GH-containing recombinant adenovirus (GHrAd) demonstrated a granular distribution of GH that colocalized with vWF. In contrast, EC infected with an rAd expressing the IgG(1) heavy chain (IG), a constitutively secreted protein, did not demonstrate colocalization of IG and vWF. In response to phorbol ester, GH as well as endogenously synthesized vWF were rapidly released from GHrAd-infected EC. By immunofluorescence microscopy, granular colocalization of GH with endogenous tissue-type plasminogen activator (tPA) was also demonstrated, and most of the tPA colocalized with vWF. These data indicate that EC are capable of selectively targeting heterologous proteins, such as GH, to the regulated secretory pathway, which suggests that EC and neuroendocrine cells share common protein targeting recognition signals or receptors.
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PMID:Targeting of a heterologous protein to a regulated secretion pathway in cultured endothelial cells. 1051 73

Several components of blood, e.g. lipids, coagulation and fibrinolytic factors, are thought to be important risk factors in cardiovascular diseases. The aim of this study was to correlate these risk factors and the soluble adhesion proteins, soluble P-selection (sP-selectin) and soluble vascular cell adhesion molecule (sVCAM-1), in healthy men and women as well as to unravel any effects of smoking. One hundred and forty-two fasting men (median age 36 years) including 39 smokers, and 124 women (median age 34 years) including 35 smokers, were tested between 0800 h and 1000 h. Fibrinogen correlated positively with white blood cells (WBC) (r = 0.25), prothrombin fragment 1.2 (F1.2) (r = 0.21), cholesterol (r = 0.27), beta-thromboglobulin (r = 0.29), Factor VII clotting activity (FVIIc) (r = 0.27) (all P < 0.0001), tissue plasminogen activator antigen (t-PAag) (r = 0.22, P < 0.0005), plasminogen activator inhibitor-1 antigen (PAI-1ag) (r= 0.20) and VCAM-1 (r= 0.19) (both P< 0.002). Cholesterol and triacylglycerol (TG) correlated positively with t-PA antigen (t-PAag) (r = 0.36 and r = 0.38), PAI-1 antigen (PAI-1ag) (r = 0.35 and r = 0.50), P-selectin (r = 0.26 and r = 0.27) (all P < 0.0001) and WBC (r = 0.17, P < 0.007 and r = 0.18, P < 0.004). Cholesterol correlated also with F1.2 (r = 0.29) and TG (r= 0.44) (P< 0.0001). In addition to cholesterol and TG, sP-selectin correlated postively with PAI-1ag (r= 0.39), t-PAag (r= 0.27) and WBC (r = 0.25) (all P < 0.0001). Comparing the various test parameters in men and women, it was found that women had significantly higher levels of F 1.2 and high-density lipoprotein-cholesterol than men, whereas men had higher levels of t-PAag, PAI-lag and P-selectin than women. Smoking was associated with a rise in several of the test parameters. It can be concluded that there are correlations between several risk factors. Of particular interest is the positive correlation between sP-selectin and a number of established risk factors of cardiovascular diseases.
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PMID:Haemostatic parameters related to lipids and adhesion molecules. 1063 57

We have investigated hemostatic parameters including platelet activation in 56 pediatric patients with or without cyanosis undergoing cardiopulmonary bypass (CPB) and cardiac surgery to repair congenital defects. Patients were participants in a study assessing the effects of tranexamic acid on surgery-related blood loss. Parameters monitored included blood loss, prothrombin F1.2, thrombin-antithrombin complexes, t-PA, PAI-1, plasminogen, fibrin D-dimer, and plasma factor XIII. Additionally, flow cytometry monitored platelet degranulation (P-selectin or CD63), as well as surface-bound fibrinogen, von Willebrand factor and factor XIIIa. Cyanotic patients had evidence of supranormal coagulation activation as both fibrin D-dimer and PAI-1 levels were elevated prior to surgery. While the extent of expression of P-selectin or CD63 was not informative, platelet-associated factor XIIIa was elevated in cyanotic patients at baseline. In both patient groups, CPB altered platelet activation state and coagulation status irrespective of the use of tranexamic acid.
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PMID:Hemostatic parameters and platelet activation marker expression in cyanotic and acyanotic pediatric patients undergoing cardiac surgery in the presence of tranexamic acid. 1066 55


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