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)

Many human thrombi lyse spontaneously without the administration of lytic drugs and cause no clinical symptoms. The mechanisms by which this occurs are incompletely understood. We found that model thrombi prepared from whole human blood in a Chandler loop also exhibited significant spontaneous lysis. Lysis was inhibited by chemical protease inhibitors, consistent with proteolysis resulting primarily from serine proteases, with a small contribution from matrix metalloproteinases. Whole blood was fractionated into platelet-rich plasma and cell populations. Significant spontaneous lysis was observed in platelet-rich thrombi enriched with polymorphonuclear leucocytes (PMNs), whereas mononuclear cells (MCs) and erythrocytes did not contribute to lysis. Incorporation of antibodies to urokinase (u-PA) and its receptor u-PAR neutralized a large proportion of the activity. Incubation of plasma with PMNs generated free u-PA activity, which was also detectable in model thrombi and in vivo human thrombi. Purified neutrophils, free of eosinophils, generated activity identical to PMNs. Smaller contributions to lysis by tissue-type plasminogen activator (t-PA), elastase and cathepsin G were also identified. These findings suggest a major role for circulating PMNs in endogenous thrombus lysis.
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PMID:Polymorphonuclear leucocytes mediate endogenous thrombus lysis via a u-PA-dependent mechanism. 1132 84

Pericellular proteolysis plays an important role in cell migration and the formation of new capillary structures. The plasminogen activator/plasmin and matrix degrading metalloproteinase (MMP) cascades act together in the remodeling of matrix and cell-matrix contacts. Previously we have shown that the formation of capillary structures by human foreskin microvascular endothelial cells (hMVECs) in a 3-dimensional fibrin matrix requires a functional urokinase-type plasminogen activator receptor (u-PAR). Here we report on the unexpected finding that inhibition of hMVEC-derived MMP activity by BB94 (batimastat) increased the outgrowth of capillary structures in a fibrin matrix. BB94 prevented the release of the u-PA binding domain D1 of u-PAR and thereby increased the number of functional u-PARs on hMVECs without affecting the u-PAR messenger RNA levels. Comparison of various types of protease inhibitors pointed to the prime involvement of MMP activity. Using recombinant MMPs it was shown that MMP-12 activity was able to release the D1 domain of cellularly expressed u-PAR. In addition, the expression of MMP-12 in control and basic fibroblast growth factor/tumor necrosis factor-alpha-stimulated hMVECs was shown by reverse transcriptase-polymerase chain reaction, suggesting that endothelial cell-derived MMP-12 may be involved in angiogenesis-related u-PAR shedding. This new mechanism of u-PAR cleavage provides new insights into the mutual interactions between the MMP and u-PA/plasmin systems. Moreover, it may be helpful in the interpretation of recent data on the use of specific MMP inhibitors in the treatment of several types of cancer.
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PMID:Proteolysis of the urokinase-type plasminogen activator receptor by metalloproteinase-12: implication for angiogenesis in fibrin matrices. 1134 39

To study the in vivo effect of all-trans-retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)) on the expression of tissue factor (TF) and the other hemostatic disturbance, a series of parameters were measured either in bone marrow blasts or plasma from acute promyelocytic leukemia (APL) patients. The plasma parameters were measured by ELISA or chromogenic studies. The TF transcription was assessed using reverse transcription-polymerase chain reaction (RT-PCR) technique. The results indicated that the blast cell procoagulant activity (PCA), TF antigen of APL cell lysate, as well as the transcription of APL TF mRNA elevated at diagnosis, were reduced after ATRA or As(2)O(3) therapy. The plasma level of P-selectin, TF, thrombin-antithrombin complex (TAT), soluble fibrinmonomer complex, thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), plasmin-antiplasmin complex, tissue plasminogen activator (t-PA) activity, urokinase plasminogen activator (u-PA) and its receptor (u-PAR), and D-dimer (D-D) significantly increased. Fibrinogen (Fg), antigen level of protein C (PC), plasminogen (PLG) activity, alpha(2)-plasminogen inhibitor activity (alpha(2)-PI), and plasminogen activator inhibitor (PAI) activity were decreased at diagnosis. The protein C activity (PC:A) and protein S (PS) remained unchanged. All the parameters were restored to normal ranges after complete remission (CR) except elevation of TF and TAT in both groups, as well as PC:A, PS, and t-PA in the ATRA group. In conclusion, there existed activation of platelets and consumption of anticoagulants as well as activation of coagulation and fibrinolytic system before treatment. Both ATRA and As(2)O(3) therapy downregulated the expression of TF mRNA, decreased the PCA and TF level in APL cells, significantly inhibited coagulation activation, corrected secondary hyperfibrinolysis and the other hemostatic abnormalities, and thus greatly improved the bleeding symptom in early stage of the treatment.
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PMID:Effects of all-trans-retinoic acid and arsenic trioxide on the hemostatic disturbance associated with acute promyelocytic leukemia. 1136 12

Bone metastases from prostate origin generate an osteoblastic reaction that is expressed in vitro by increased osteoblast proliferation. The urokinase-like plasminogen activator (u-PA) present in the media conditioned by tumoral prostatic cells acting as a ligand of the cellular membrane receptor (u-PAR), has been identified as the specific factor that modulates this proliferative reaction. The present study represents an effort to unravel the intracellular pathway by which u-PA activates osteoblastic proliferation and to evaluate the role of cellular receptor u-PAR in this proliferative phenomenon. Our results show that in vitro u-PA stimulates proliferation of SaOS-2 osteoblastic cells by activating the MAP kinase route of ERK 1 and 2 and the p38 pathway. These results are in accordance with the inhibition of intermediate activation and cell proliferation by PD 098059 and SB 203580, specific inhibitors of MEK and p38, respectively. We also show that SaOS-2 cells increase their proliferative response when cells are plated onto vitronectin, the second natural ligand of u-PAR, and that culturing SaOS-2 cells in the presence of u-PA represents a stimuli for u-PAR expression. On the basis of these results we propose that osteoblastic cells respond to the prostate-derived u-PA stimuli in a very efficient manner that includes the utilization of two different signaling routes and the stimulation of the expression of the u-PA receptor.
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PMID:ERK 1,2 and p38 pathways are involved in the proliferative stimuli mediated by urokinase in osteoblastic SaOS-2 cell line. 1150 Sep 57

Laryngeal cancer is the most common neoplasm of the head and neck region. Laryngeal cancer patients experience thromboembolic complications more often than the general population. Our previous studies revealed in loco activation of blood coagulation in laryngeal cancer. The purpose of the present study was to examine the interactions among the laryngeal cancer cells and fibrinolytic system components in loco. Twenty-two cases of squamous carcinoma of the larynx were examined. AMeX method-preserved cancer tissues were examined using immunohistochemical ABC method. Fibrin and D-D fibrin dimers were demonstrated in the matrix, predominantly on the tumor-host front. Plasminogen, tissue-type plasminogen activator (t-PA) and plasmin were detected in cancer cells, but the intensity of their expression revealed a negative correlation with the degree of malignancy. A weak expression of high molecular weight urokinase (HMW-UK) was observed in cancer cells in the centers of the cancer foci, and a product of its degradation--low molecular weight urokinase (LMW-UK) was observed in cancer cells on the invasion front. The presence of plasminogen activator inhibitors (PAI-1, PAI-2, PAI-3) was also documented in the cancer cells. The expression of urokinase receptor (u-PAR) was very weak. Based on the results of the study, we suggest that in laryngeal cancer a suboptimal activation of fibrinolysis occurs that contributes to fibrin deposition in the tumour.
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PMID:[The location of components of fibrinolytic system in laryngeal cancer]. 1459 67

The growth rate of vascular smooth muscle cells (VSMCs), which were derived from aorta of mice deficient in the fibrinolytic factors tissue-type plasminogen activator (t-PA(-/-)), urokinase (u-PA(-/-)), u-PA receptor (u-PAR(-/-)) and type 1 plasminogen activator inhibitor (PAI-1(-/-)), as well as wild-type (WT) mice, was investigated in the presence of mouse melanoma cells (B16). In the VSMCs cultured with a basal medium supplemented with 10% fetal calf serum (FCS), there was no difference in the growth rate among the gene-lacking VSMCs and WT VSMCs, indicating that these fibrinolytic factors were not involved in the FCS-mediated cell proliferation. On the other hand, when these VSMCs were cultured with B16 cells in either the mixed culture or a double-chamber, only u-PAR(-/-) VSMCs showed a significantly lower growth rate. In addition, these suppressive effects on u-PAR(-/-) VSMCs were also observed in the presence of B16-derived conditioned medium (B16/CM). The growth rate of all the VSMCs except u-PAR(-/-) VSMCs was increased in the presence of B16/CM. The degree of the increase in cell number was comparable to that obtained with FCS. These effects on growth activity were partially associated with the levels of mitogen-activated protein kinase (MAPK, p42/p44) activity. The findings suggest that u-PAR plays an important role in the proliferative response of VSMCs and that without u-PAR, there is no intracellular signaling for cell proliferation.
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PMID:Growth inhibition of vascular smooth muscle cells derived from urokinase receptor (u-PAR)-deficient mice in the presence of carcinoma cells. 1508 64

The aim of the study was to evaluate dynamic changes in the expression of fibrinolytic system components in neointima forming in polyester vascular grafts. The study was carried out on 18 mongrel dogs divided into three groups, that underwent replacement of abdominal aorta with a polyester double velour prosthesis. Grafts were removed at 1, 4 and 12 months. The specimens were fixed according to AMeX method. Immunohistochemical labeling for von Willebrand factor (vWf), tissue plasminogen activator (t-PA), urokinase (u-PA), its receptor (u-PAR), plasminogen activator inhibitor type 1 (PAI-1) and D-dimer (DD) was performed. Increasing intensity of vWf expression on the graft luminal surface was found in successive periods of the study. A light positive t-PA and u-PA staining was shown in neointima at 1 month and its intensity was significantly increased at 4 and 12 months. Expression of u-PAR appeared at 4 months. A light positive PAI-1 and DD staining was demonstrated in neointima in all periods of the study. The results demonstrated increasing expression of fibrinolysis activators in neointima of polyester vascular grafts. Intensive expression of plasminogen activators, when compared to their inhibitor may reduce thrombotic properties of graft neointima particularly in the late period after prosthesis implantation.
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PMID:Expression of fibrinolysis activators and their inhibitor in neointima of polyester vascular grafts. 1518 13

We characterized the tracheal and bronchial relaxation caused by proteinase-activated receptor-2 (PAR-2) activation in ddY mice and/or in wild-type and PAR-2-knockout mice of C57BL/6 background. Ser-Leu-Ile-Gly-Arg-Leu-amide (SLIGRL-NH(2)) and Thr-Phe-Leu-Leu-Arg-amide, PAR-2- and PAR-1-activating peptides, respectively, caused relaxation in the isolated ddY mouse trachea and main bronchus. The relaxation was abolished by specific inhibitors of cyclooxygenase (COX)-1, COX-2, mitogen-activated protein kinase kinase (MEK), and p38 MAP kinase. The MEK and p38 MAP kinase inhibitors did not affect prostaglandin E(2)-induced relaxation. Inhibitors of cytosolic Ca(2+)-dependent phospholipase A(2) (PLA), Ca(2+)-independent PLA(2), diacylglycerol lipase, tyrosine kinase, and protein kinase C exhibited no or only minor inhibitory effects on the PAR-mediated relaxation. Trypsin, a PAR-2 activator, and 2-furoyl-Leu-Ile-Gly-Arg-Leu-amide, a potent PAR-2-activating peptide, in addition to SLIGRL-NH(2), caused airway relaxation in wild-type C57BL/6 mice, as in ddY mice. In PAR-2-knockout mice, the peptide effects were absent and the potency of trypsin decreased. Desensitization of PAR-2 and/or PAR-1 greatly suppressed the relaxant effect of trypsin. The bronchial and tracheal tissues displayed distinct sensitivities toward trypsin and the PAR-2-activating peptides. Our data indicate an involvement of both COX-1 and COX-2, and the MEK-extracellular signal-regulated kinase and p38 MAP kinase signaling pathways in the PAR-2- and PAR-1-triggered relaxation of mouse airway tissue, and substantiate a role for PAR-2 in regulating both the trachea and bronchial responsiveness in the mouse lung.
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PMID:Proteinase-activated receptor-2-mediated relaxation in mouse tracheal and bronchial smooth muscle: signal transduction mechanisms and distinct agonist sensitivity. 1519 93

It is now generally accepted that factor XII (FXII) binds to cellular surfaces in the vascular system. One of the suggested receptors of this binding is the glycosylphosphatidylinositol-anchored urokinase-like plasminogen activator (u-PAR) harbored in caveolae/lipid rafts. However, binding of FXII to human umbilical vein endothelial cells (HUVEC) has never been shown to be localized to these specialized membrane structures. Using microscopical techniques, we here report that FXII binds to specific patches of the HUVEC plasma membrane with a high density of caveolae. Further investigations of FXII binding to caveolae were performed by sucrose density-gradient centrifugations. This showed that the majority of FXII, chemically cross-linked to HUVEC, could be identified in the same fractions of the gradient as caveolin-1, a marker of caveolae, while the majority of u-PAR was identified in noncaveolae lipid rafts. Accordingly, cholesterol-depleted cells were found to bind significantly reduced amounts of FXII. These observations, combined with the presence of a minority of u-PAR in caveolae concomitant with FXII binding, indicate that FXII binding to u-PAR may be secondary and depends upon the structural elements within caveolae. Thus, FXII binding to HUVEC depends on intact caveolae on the cellular surface.
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PMID:Factor XII binding to endothelial cells depends on caveolae. 1523 96

The hepatocyte growth factor (HGF) is a multifunctional cytokine that is produced as latent scHGF (single chain HGF). Various proteases reportedly cleave scHGF to generate the active two-chain form (HGF), including u-PA (urokinase-type plasminogen activator), t-PA (tissue-type plasminogen activator), kallikrein, Factor XIa, Factor XIIa, HGF activator and matriptase. Considerable evidence indicates that, in vivo, u-PA activates scHGF in the liver; however, the in vivo results have not been uniformly supported by in vitro experiments. We now report that cleavage of scHGF by high-molecular-mass u-PA (abbreviated u-PA throughout) is sensitive to ionic strength. scHGF cleavage by u-PA was accelerated as the ionic strength was decreased. This result was equivalent irrespective of whether the predominant anion was chloride or acetate. Lmw-u-PA (low-molecular-mass u-PA) was ineffective at cleaving scHGF, regardless of ionic strength. Although scHGF shares homology with plasminogen, EACA (-amino-caproic acid) did not regulate u-PA-mediated scHGF cleavage. Soluble HGF receptor (MET) and soluble u-PAR (u-PA receptor) inhibited the scHGF cleavage. These results support a model in which the ability of u-PA to activate scHGF in vivo may be highly dependent on local conditions within the extracellular space.
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PMID:Activation of hepatocyte growth factor by urokinase-type plasminogen activator is ionic strength-dependent. 1586 63


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