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)

VEGF has been proposed to participate in normal and pathological vessel formation. Surprisingly, lack of only a single VEGF allele resulted in embryonic lethality due to abnormal formation of intra- and extra-embryonic vessels. Homozygous VEGF-deficient embryos, generated by tetraploid aggregation, revealed an even more severe defect in vessel formation. These results (1) suggest a tight regulation of early vessel development by VEGF and, indirectly, the presence of other VEGF-like molecules; (2) reveal an unprecedented lethal phenotype associated with heterozygous deficiency of an autosomal gene, and (3) demonstrate that tetraploid aggregation was a valid and the only method to study the phenotype of the homozyogous VEGF-deficient embryos. The dominant and strict dose-dependent role of VEGF in vivo renders this molecule a desirable therapeutic target for promoting or preventing angiogenesis. Tissue factor (TF) is the principal cellular initiator of coagulation and its deregulated expression has been related to thrombogenesis in sepsis, cancer, and inflammation. However, TF appears to be also involved in a variety of non-hemostatic functions including inflammation, cancer, brain function, immune response, and tumor-associated angiogenesis. Surprisingly, TF deficiency resulted in embryonic lethality due to abnormal extra-embryonic vessel development and defective vitelloembryonic circulation. The abnormal yolk sac vasculature is reminiscent of that observed in embryos lacking VEGF, possibly suggesting that both gene functions are interconnected. These targeting studies extend the recently documented role of TF in tumor-associated angiogenesis and warrant further study of its role in angiogenesis during other pathological disorders. The plasminogen system, via its triggers, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), has been implicated in thrombosis, arterial neointima formation, and atherosclerosis. Studies in mice with targeted gene inactivation of t-PA, u-PA, PAI-1, the urokinase receptor (u-PAR), and plasminogen (Plg) revealed (1) that deficiency of t-PA or u-PA increase the susceptibility to thrombosis associated with inflammation and that combined deficiency of t-PA:u-PA or deficiency of Plg induces severe spontaneous thrombosis; (2) that vascular injury-induced neointima formation is reduced in mice lacking u-PA-mediated plasmin proteolysis, unaltered in t-PA- or u-PAR-deficient mice and accelerated in PAI-1-deficient mice, but that it can be reverted by adenoviral PAI-1 gene transfer; and (3) that atherosclerosis in mice doubly deficient in apolipoprotein E (apoE) and PAI-1 is reduced after 10 weeks of cholesterol-rich diet. Thus, the plasminogen system significantly affects thrombosis, restenosis, and atherosclerosis.
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PMID:Insights in vessel development and vascular disorders using targeted inactivation and transfer of vascular endothelial growth factor, the tissue factor receptor, and the plasminogen system. 918 98

Angiotensin converting enzyme inhibitors (ACE-I) have been reported to prevent the recurrence of cardiovascular events. The mechanism of this decrease, however, can not be completely explained by anti-hypertensive and anti-hypertrophic effects of ACE-I. To investigate the mechanism of this decrease, we studied the regulation of plasminogen activator inhibitor-1 (PAI-1), tissue type plasminogen activator (TPA), tissue factor (TF), and tissue factor pathway inhibitor (TFPI) by angiotensin II (Ang II) in cultured rat aortic endothelial cells. Ang II increased PAI-1 and TF mRNA expression without affecting that of TPA or TFPI. These inductions were accompanied by increases in PAI-1 and TF activities and were inhibited by a type I Ang II receptor antagonist. The results suggest that Ang II decreases the antithrombotic properties of endothelial cells which increases the chance of thrombosis. Thus, inhibition of the renin-angiotensin system may be beneficial to prevent thrombus formation in treatment of ischemic heart disease.
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PMID:Angiotensin II increases plasminogen activator inhibitor-1 and tissue factor mRNA expression without changing that of tissue type plasminogen activator or tissue factor pathway inhibitor in cultured rat aortic endothelial cells. 924 56

Quantitative reverse transcription polymerase chain reaction and in situ hybridization were employed to investigate the expression of tissue-type and urokinase-type plasminogen activators (t-PA and u-PA, respectively), of their specific inhibitor (PAI-1), and of the procoagulant molecule tissue factor (TF) in tissues from mice that develop autoimmune disease (MRL lpr/lpr). A dramatic increase in PAI-1 activity in plasma and in PAI-1 mRNA in the kidneys was observed in these mice, and this increase appeared to correlate with the progression of lupus nephritis. The increase in PAI-1 mRNA was relatively specific for the kidney as little or no change was observed in most other tissues. One exception was the brain where PAI-1 mRNA was also significantly higher in the diseased mice. In addition to these changes in PAI-1, decreases in u-PA mRNA and increases in TF mRNA were demonstrated in kidneys from the lupus-prone mice. These changes also correlated with the development of lupus nephritis and with spontaneous glomerular and peritubular fibrin deposition in the nephritic kidney. In this regard, the MRL lpr/lpr mice were found to be considerably more sensitive to endotoxin than the normal controls, developing fibrin deposits in the kidneys and other tissues at 10- to 20-fold lower concentrations of this toxic agent. The increase in PAI-1 and TF mRNAs and the decrease in u-PA mRNA in the kidneys of MRL lpr/lpr mice suggests that changes in the expression of these genes may promote the formation of microthrombi and thus contribute to the progression of lupus nephritis in this model.
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PMID:The kidneys of mice with autoimmune disease acquire a hypofibrinolytic/procoagulant state that correlates with the development of glomerulonephritis and tissue microthrombosis. 928 21

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

Two in vitro models are compared to investigate whether cellular configuration or composition of the matrix in which the cells are cultured influences growth and/or prognostic parameters. T47D, MCF-7 and Hs578T breast cancer cell lines were cultured on two different matrices (agarose and collagen). Growth curves, biological markers (Ki-67, p53 and bcl-2) and the expression of hemostatic parameters were studied. The tested hemostatic parameters were urokinase-type plasminogen activator, tissue-type plasminogen activator and plasminogen activator inhibitor as fibrinolytic parameters and von Willbrand factor, tissue factor, antithrombin III, factor X and factor Xa as coagulation parameters. We found that T47D and MCF-7 formed spheroids in both matrices. Hs578T did not form spheroids; instead, the cells remained single cells in the agarose matrix and grew invasively through the collagen matrix. Expression of the biological markers was similar for spheroids and monolayers. In contrast, a clear difference in expression of hemostatic factors by spheroids and monolayers was found.
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PMID:Cellular arrangement of human breast cancer cell lines determines hemostatic parameters. 948 61

Tissue factor (TF) has been implicated in several important biologic processes, including fibrin formation, atherogenesis, angiogenesis, and tumor cell migration. In that plasminogen activators have been implicated in the same processes, the potential for interactions between TF and the plasminogen activator system was examined. Plasminogen was found to bind directly to the extracellular domain of TF apoprotein (amino acids 1-219) as determined by optical biosensor interaction analysis. A fragment of plasminogen containing kringles 1 through 3 also bound to TF apoprotein, whereas isolated kringle 4 and miniplasminogen did not. Expression of TF on the surface of a stably transfected Chinese hamster ovary (CHO) cell line stimulated plasminogen binding to the cells by 70% more than to control cells. Plasminogen bound to a site on the TF apoprotein that appears to be distinct from the binding site for factors VII and VIIa as judged by a combination of biosensor and cell assays. TF enhanced two-chain urokinase (tcuPA) activation of Glu-plasminogen, but not of miniplasminogen, in a dose-dependent, saturable manner (half maximal stimulation at 59 pmol/L). TF apoprotein induced an effect similar to that of relipidated TF, but a relatively higher concentration of the apoprotein was required (half maximal stimulation at 3.8 nmol/L). The stimulatory effect of TF on plasminogen activation was confirmed when plasmin formation was examined directly on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In accord with this, TF inhibited fibrinolysis by approximately 74% at a concentration of 14 nmol/L and almost totally inhibited the binding of equimolar concentrations of plasminogen to human umbilical vein endothelial cells and human trophoblasts. Further, CHO cells expressing TF inhibited uPA-mediated fibrinolysis relative to a wild-type control. TF apoprotein and plasminogen were found to colocalize in atherosclerotic plaque. These data suggest that plasminogen localization and activation may be modulated at extravascular sites through a high-affinity interaction between kringles 1 through 3 of plasminogen and the extracellular domain of TF.
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PMID:Tissue factor regulates plasminogen binding and activation. 949 Jun 81

Statins are most potent lipid-lowering drugs. The mechanisms of their action is specific inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) activity. HMG-CoA reductase catalyses the reduction of HMG-CoA o mevalonate and is rate-limiting step in cholesterol biosynthesis pathway. Mevalonate is considered to be not only an important intermediate of cholesterol synthesis, but also the source of isoprenoids which play important role in DNA replication and cell growth. It was shown that statins inhibit the proliferation and migration of vascular smooth muscle cell--key events in atherogenesis. HMG-CoA reductase inhibitors lower the reactivity of arterial wall to vasoconstrictor agents, decrease the concentration of lipoprotein [a]--an independent risk factor of atherosclerosis, inhibit the generation of free radicals and lipid peroxidation, decrease the number of macrophages in atherosclerotic lesion and finally, equilibrate the clotting-fibrynolysis processes of attennuating platelets function, reducing the tissue factor synthesis and decreasing the concentration of plasminogen activator inhibitors. Statins are presently considered by NCEP to be the drugs of first choice for treatment of hypercholesterolemia.
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PMID:[Anti-atherosclerotic actions of HMG-CoA reductase inhibitors]. 950 89

In patients with sepsis and septic shock, both coagulation and fibrinolysis are activated frequently leading to the syndrome of diffuse intravascular coagulation (DIC). The different mechanisms leading to abnormalities in coagulation and fibrinolysis are discussed in detail. The coagulation and fibrinolytic system appear to be influenced by the septic process largely independently, leading to a procoagulant imbalance between these systems. Coagulation is initiated by mediator-induced expression of tissue factor and is associated with consumption of the natural coagulation inhibitors antithrombin III, protein C, and protein S. As a result, high plasma levels of thrombin-antithrombin complex (TAT) can be found. The effects on fibrinolysis are dominated by (highly) increased levels of plasminogen activator inhibitor type 1 (PAI-1), leading to inadequate fibrinolysis. Although levels of plasminogen activator antigen are increased, its activity is almost completely inhibited by PAI-1. The resulting effects predispose to a procoagulant state, with widespread fibrin deposition, which may be an important mechanism contributing to multiple organ failure. A thorough understanding of the pathophysiological mechanisms underlying the DIC-syndrome is a prerequisite for a rational approach and future therapy for this severe complication of sepsis.
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PMID:Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock. 951 78

We monitored 30 laboratory hemostatic parameters in an attempt to better comprehend alterations in coagulation and fibrinolysis in 10 patients with hematological malignancies subjected to autologous peripheral blood stem cell transplantation (APBSCT). These parameters were assessed before and just after high-dose conditioning chemotherapy, on days 1, 7, 14 and 28. Although, clinical manifestations associated with fibrino-coagulation disorders never occurred, including veno-occlusive disease, a statistically significant increase was seen in 7 of 30 parameters, compared to values seen before conditioning chemotherapy. These were subdivided into early and late phase parameters. The early phase parameters, which increased during the first day after the conditioning chemotherapy was given, then returned to baseline values, included protein C, plasma tissue factor and tissue-plasminogen activator. The late phase parameters, which increased over baseline values during days 7 to 28, included free-protein S, fibrinogen, plasmin-alpha2-plasmin inhibitor complex and soluble-thrombomodulin. The increase of early phase parameters, as produced by the liver and by endothelial cells, may reflect tissue damage by conditioning chemotherapy. Late phase parameters increased in parallel with C-reactive protein, which suggests a correlation with the degree of inflammation, such as the presence of infective disease during neutropenia. These subclinical alterations in coagulation and fibrinolysis which take on a biphasic pattern during the course of APBSCT should be kept in mind by the attending physicians during therapy.
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PMID:Subclinical alterations in coagulation and fibrinolysis in patients undergoing autologous peripheral blood stem cell transplantation. 951 13

beta2-Glycoprotein I (beta2GPI) is a highly glycosylated plasma protein with the ability to bind negatively charged substances such as DNA, heparin, dextran sulfate, and negatively charged phospholipids. The most relevant physiological role of beta2GPI is supposed to be the regulation of the function of anionic phospholipids like cardiolipin (CL). beta2GPI consists of a single polypeptide chain (326 amino acid residues) with a molecular mass of about 50 kD and with five tandem repeated domains (I, II, III, IV, and V). In the previous study, we found that factor Xa can produce the nicked form by cleaving Lys 317-Thr 318, using recombinant human domain V (r-Domain V). However, the reaction was extremely slow. In the present paper, we found that plasmin can produce the nicked form of domain V, using recombinant domain V (r-Domain V) and beta2GPI from human plasma. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, r-Domain V was rapidly cleaved into a nicked form by plasmin, very slowly by factor Xa, but not by thrombin, tissue-type plasminogen activator, urokinase, and tissue factor/factor VIIa. The cleavage site of r-Domain V and beta2GPI by plasmin was proved to be Lys 317-Thr 318 by amino acid sequence analysis of the digest and of the C-terminal peptide isolated by high-performance liquid chromatography. The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI. To determine whether the specific cleavage of beta2GPI by plasmin can occur also in plasma, human plasma was first acid-treated to inactivate alpha2PI and then incubated with urokinase. About 12% of beta2GPI in plasma was nicked when alpha2PI activity decreased to 80%. The nicked form was not generated in plasminogen-depleted plasma. These results suggest that plasmin can produce the nicked form of beta2GPI with the reduced ability to bind phospholipids in vivo.
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PMID:Plasmin can reduce the function of human beta2 glycoprotein I by cleaving domain V into a nicked form. 959 64


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