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)

Two in vitro models of coronary thrombolysis in man, i.e. dislodgement of thrombi formed from non-anticoagulated human blood, either by (i) shear-stress or (ii) interaction of platelets with type I collagen fibre, were studied. Heparinization (1 U/ml) of blood prior to thrombus formation by (i) strongly inhibited spontaneous dislodgement (P less than 0.0001). Heparin (1 U/ml), when added with streptokinase (SK) or tissue-type plasminogen activator (rt-PA) prior to thrombus formation, considerably delayed thrombolysis. Furthermore, thrombolysis occurred much earlier when thrombi were perfused with SK or rt-PA in native than in heparinized blood. Heparin inhibited binding of 125I-rt-PA (17%, P less than 0.02) and plasminogen (88%, P less than 0.0005) to platelets activated by ADP in citrated platelet-rich plasma. We conclude that heparin interferes with the fibrinolytic system at the surface of activated platelets. Our findings suggest that heparin administration prior to thrombolytic therapy for acute myocardial infarction should be questioned.
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PMID:Heparin inhibits spontaneous thrombolysis and the thrombolytic effect of both streptokinase and tissue-type plasminogen activator. An in vitro study of the dislodgement of platelet-rich thrombi formed from native blood. 210 72

To understand the mechanisms regulating osteoid removal by osteoblasts, mouse calvarial osteoblasts were grown on 14C-labelled type I collagen films and stimulated with 1,25-dihydroxyvitamin D-3 (2.5.10(-8) M) for 48-72 h. In the presence of 5% non-inhibitory rabbit serum this resulted in a 2-3-fold increase in collagen degradation and a dramatic change in osteoblast morphology, when compared with untreated osteoblasts. Collagenolysis was accompanied by increased synthesis and release of latent collagenase, gelatinase and stromelysin and a concomitant decrease in their specific inhibitor, TIMP (tissue inhibitor of metalloproteinases). In serum-free medium, osteoblasts failed to degrade collagen, but their ability to lyse collagen could be restored by adding plasminogen (5 micrograms/ml) to the cultures. Plasminogen-dependent collagenolysis was inhibited by human recombinant TIMP (5 units/ml), demonstrating that plasmin, derived from plasminogen, activated latent collagenase and did not itself degrade collagen. Plasminogen activator production was confirmed by culturing osteoblasts on 125I-labelled fibrin plates. Comparison with urokinase-type and tissue-type plasminogen activator standards suggested that osteoblast plasminogen activator was predominantly cell-associated and likely to be of the urokinase type. Immunocytochemistry indicated that osteoblasts also constitutively produce plasminogen activator inhibitor-1. These findings provide evidence for the involvement of a plasminogen-plasmin-latent metalloproteinase activation cascade in type I collagen degradation by osteoblasts, and for its regulation by TIMP and plasminogen activator inhibitor-1.
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PMID:Type I collagen degradation by mouse calvarial osteoblasts stimulated with 1,25-dihydroxyvitamin D-3: evidence for a plasminogen-plasmin-metalloproteinase activation cascade. 255 72

FPLC anion-exchange and chromatofocusing chromatography were used to purify the major neutral proteinase from secretions of axenically cultured Entamoeba histolytica trophozoites. HM-1 strain trophozoites, which were more proteolytically active than the less virulent HK-9 strain, were used for purification of the enzyme. It is a thiol proteinase with a subunit Mr of approximately 56,000, a neutral pH optimum, and a pI of 6. The importance of this enzyme in extraintestinal amoebiasis is suggested by its ability to degrade a model of connective tissue extracellular matrix as well as purified fibronectin, laminin, and type I collagen. The enzyme caused a loss of adhesion of mammalian cells in culture, probably because of its ability to degrade anchoring proteins. Experiments with a peptide substrate and inhibitors indicated that the proteinase preferentially binds peptides with arginine at P-1. It is also a plasminogen activator, and could thus potentiate host proteinase systems.
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PMID:The major neutral proteinase of Entamoeba histolytica. 286 98

Epidermal growth factor (EGF) stimulates the migration and proliferation of, and tissue-type plasminogen activator (tPA) synthesis in, human omental microvascular endothelial (HOME) cells in culture, as well as inducing the formation by these cells. In the present study, we examined the effects of various growth factors, i.e., transforming growth factor-alpha (TGF-alpha), insulin-like growth factor 1 (IGF-1), and hepatocyte growth factor (HGF) on HOME cells, and compared their effects with that of EGF. IGF-1 stimulated the proliferation and migration of these cells at a level comparable to EGF. EGF and TGF-alpha induced expression of tPA in HOME cells, while IGF-1 and HGF did not. EGF and TGF-alpha induced tube formation by HOME cells in type I collagen gel, while IGF-1 and HGF did not. The stimulatory effect of EGF on tube formation in the gel was blocked by anti-tPA antibody and by a serine protease inhibitor, aprotinin. When exogenous tPA and IGF-1 or HGF were added simultaneously to the culture, a marked induction of tube formation in the gel was observed. Exogenously added tPA alone, however, had no such inducible effect on tube formation. These results indicated an indispensable role of tPA in growth factor-dependent tube formation by HOME cells. Two subsets of growth factors appeared to modulate angiogenesis: One with fully active angiogenic activity which could induce PA (this included EGF and TGF-alpha), and the other, which could not induce PA and was not angiogenic, but could promote angiogenesis in the presence of PA. This subset included IGF-1 and HGF.
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PMID:Indispensable role of tissue-type plasminogen activator in growth factor-dependent tube formation of human microvascular endothelial cells in vitro. 767 96

This paper assesses alterations in collagen metabolism following thrombolytic therapy of acute myocardial infarction with tissue-plasminogen activator. Sequential serum measurements of the amino-terminal propeptide of type III procollagen (S-PIIINP) and the carboxyterminal propeptide of type I collagen (S-PICP) in patients suspected of acute myocardial infarction randomized to tissue-plasminogen activator or placebo were used. S-PIIINP increased at 3 h in patients with acute myocardial infarction treated with tissue-plasminogen activator (P < 0.05). S-PIIINP was higher in patients treated with tissue-plasminogen activator compared with placebo-treated patients at 3 and 6 h (P < 0.05). S-PICP decreased independently of therapy and diagnosis. Tissue-plasminogen activator, therefore, induces breakdown of collagen, some of which is located in the wall of atheromatous arteries. Vascular patency following thrombolytic therapy may partly be mediated by breakdown of thrombogenic collagen in the vessel wall. The findings may suggest a role for S-PIIINP as a non-invasive indicator of the risk of reocclusion.
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PMID:Effect on collagen metabolism of thrombolytic therapy with tissue-plasminogen activator. A randomized, placebo-controlled study. 770 81

Hepatocyte growth factor/scatter factor (HGF/SF) and keratinocyte growth factor (KGF, also designated FGF-7) are paracrine growth factors secreted by mesenchymal cells and active on a variety of epithelial cell types. In this study, the biologic responses of keratinocytes to these paracrine growth factors were compared. Stimulation of mitogenesis, migration, plasminogen activator (PA) activity, and fibronectin production were examined using human foreskin keratinocytes cultured in serum-free MCDB 153 medium. Although the two factors stimulated a similar level of proliferation when cells were maintained for 5 d in 1.8 mM Ca++, the peak effect of KGF, observed at 10 ng/ml, was approximately threefold higher than that of HGF/SF when cells were in medium containing 0.15 mM Ca++. Both agents promoted the migration of cells in low-calcium medium (0.08 mM Ca++). However, the magnitude of the response was approximately twofold greater for HGF/SF at 10 ng/ml than KGF at the same concentration. None of the matrix proteins such as type I collagen, type IV collagen, laminin, or fibronectin either stimulated or suppressed HGF/SF- or KGF-stimulated keratinocyte migration. Both factors stimulated PA activity of the cell extracts, especially urokinase-type, with similar potencies. Promoted PA activity was maximal with the addition of 10 ng/ml of either factor. Neither factor increased the production of fibronectin under conditions in which transforming growth factor-beta 1 was active. These results indicate that HGF/SF and KGF, both recognized as paracrine growth factors, elicit distinctive patterns of response by keratinocytes, implying that they have different roles in epidermal physiology.
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PMID:Comparative study of hepatocyte growth factor/scatter factor and keratinocyte growth factor effects on human keratinocytes. 776 66

In WEHI-3B murine leukemic cells, plasminogen activator and plasminogen binding sites are associated with the cell membrane. The putative receptor for the zymogen exhibits low affinity for the ligand (dissociation constant of 0.38 microM and a high binding capacity (40,000 sites per cell). Plasminogen also binds in a cooperative fashion to type I collagen with an affinity which is higher than that displayed by cells. Collagen-bound plasminogen can be activated by cells preincubated with plasminogen in a manner that cells develop the capacity to adhere to type I collagen. The activation of collagen-bound plasminogen by cellular urokinase-like plasminogen activator (u-PA) was 60% more efficient than the activation of the soluble (not bound) form of plasminogen. These results suggest that in the invasive phenomena, WEHI cells operate as carriers of plasminogen from plasma to tissue. In addition, collagen can serve as a reservoir of zymogen in the extracellular matrix milieu through direct binding to plasminogen and at the same time allow more efficient plasminogen activation.
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PMID:Surface-associated plasminogen activation in leukemic cells: interaction with extracellular matrix. 781 13

Tube formation in collagen gel was induced in human omental microvascular endothelial (HOME) cells in the presence of epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha). TGF-alpha enhanced the expression of the tissue type plasminogen activator (t-PA) gene, whereas TGF-beta increased the expression of the PA inhibitor-1 (PAI-1) gene and inhibited that of the t-PA gene. TGF-beta inhibited the tube formation of HOME cells in type I collagen gel that was enhanced in response to TGF-alpha. We have recently established an angiogenesis model in vitro in which vascular endothelial cells on type I collagen gel in an inner chamber are co-cultured with other types of cells in an outer chamber. Here we examined whether the EGF/TGF-alpha-induced tube formation in HOME cells was modulated by human chondrocytes co-culture in the outer chamber. TGF-alpha-dependent tube formation of HOME cells was inhibited when human chondrocytes were co-cultured in the outer chamber. This chondrocyte-induced inhibition of tube formation was partly abrogated by co-administration of anti-TGF-beta antibody. These findings suggest that TGF-beta is partly involved in the human chondrocyte-dependent inhibition of tube formation by human microvascular endothelial cells. This is the first model system demonstrating that avascularity of human chondrocytes is partly due to TGF-beta family produced from them.
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PMID:Inhibition of tubular morphogenesis in human microvascular endothelial cells by co-culture with chondrocytes and involvement of transforming growth factor beta: a model for avascularity in human cartilage. 794 24

During angiogenesis capillary endothelial cells undergo a coordinated set of modifications in their interactions with extracellular matrix components. In this study we have investigated the effect of the prototypical angiogenic factor basic fibroblast growth factor (bFGF) on the expression and function of several integrins in microvascular endothelial cells. Immunoprecipitation experiments with antibodies to individual subunits indicated that microvascular cells express at their surface several integrins. These include the alpha 1 beta 1, alpha 2 beta 1, and alpha 3 beta 1 laminin/collagen receptors; the alpha 6 beta 1 laminin receptor; the alpha 5 beta 1 and alpha v beta 1 fibronectin receptors; the alpha 6 beta 4 basement membrane receptor; and the alpha v beta 3 and alpha v beta 5 vitronectin receptors. Treatment with bFGF caused a significant increase in the surface expression of the alpha 2 beta 1, alpha 3 beta 1, alpha 5 beta 1, alpha 6 beta 1, alpha 6 beta 4, and alpha v beta 5 integrins. In contrast, the level of expression of the alpha 1 beta 1 and alpha v beta 3 integrins was decreased in bFGF-treated cells. Immunoprecipitation of metabolically labeled cells indicated that bFGF increases the biosynthesis of the alpha 3, alpha 5, alpha 6, beta 4, and beta 5 subunits and decreases the production of the alpha v and beta 3 subunits. These results suggest that bFGF modulates integrin expression by altering the biosynthesis of individual alpha or beta subunits. In accordance with the upregulation of several integrins observed in bFGF-treated cells, these cells adhered better to fibronectin, laminin, vitronectin, and type I collagen than did untreated cells. The largest differences in beta 1 integrin expression occurred approximately 72 h after exposure to bFGF, at a time when the expression of the endothelial cell-to-cell adhesion molecule endoCAM was also significantly upregulated. In contrast, a shorter exposure to bFGF (24-48 h) was required for the maximal induction of plasminogen activator production in the same cells. Taken together, these results show that bFGF causes significant changes in the level of expression and function of several integrins in microvascular endothelial cells.
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PMID:Basic fibroblast growth factor modulates integrin expression in microvascular endothelial cells. 829 94

The effect of fibrin on angiogenesis in vitro was investigated using an experimental model of tube formation by bovine capillary endothelial cells (BCEs) in type I collagen gel. One milligram per milliliter of fibrin added into type I collagen gel significantly increased the length of the tubular structures formed by BCEs in the gel by about 180% compared with type I collagen only. The facilitating effect of fibrin on tube formation by BCEs was inhibited by either anti-basic fibroblast growth factor (bFGF) IgG (25 micrograms/ml) or anti-urokinase type plasminogen activator (uPA) IgG (10 micrograms/ml) added to the gel and culture medium, but not by anti-tissue type plasminogen activator (uPA) IgG (10 micrograms/ml) added to the gel and culture medium, but not by anti-tissue type plasminogen activator (10 micrograms/ml) or non-immune IgG. The Arg-Gly-Asp (RGD) containing peptides (100 micrograms/ml) added to the culture medium also suppressed tube formation by BCEs in fibrin-containing type I collagen gel, but not in type I collagen gel. These results suggest that the increased release of bFGF and uPA by BCEs therefore plays a role in the angiogenic effect of fibrin in vitro, and the angiogenic effect of fibrin is mediated by the RGD sequence in fibrin, probably via the function of integrin receptor of the BCEs.
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PMID:Effects of fibrin on the angiogenesis in vitro of bovine endothelial cells in collagen gel. 858 91


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