Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of transforming growth factor-beta (TGF-beta) was analyzed on the synthesis of fibronectin, collagen type IV, and urokinase plasminogen activator in human glomerular epithelial cells in culture. An increase in the abundance of specific mRNA was found for collagen type IV and fibronectin. Fibronectin protein synthesis was also increased in TGF-beta treated cells; most of the de novo synthesized fibronectin was found as an unsoluble protein associated with extracellular matrix. In the same cells the amount of plasminogen activator mRNA was found leading also to a decreased surface expression of urokinase plasminogen activator. The data support the concept that by upregulating matrix protein synthesis and downregulating the plasminogen activator system, TGF-beta favors the development of sclerosis.
 ...
PMID:Interaction of transforming growth factor beta 1 with human glomerular epithelial cells in culture: opposite effects on synthesis of matrix proteins and on urokinase plasminogen activator. 884 65

Smooth muscle cell (SMC) migration is an early response to vascular injury and contributes to the development of intimal thickening. Upregulation of several components of the plasminogen activator (PA) system has been documented after vascular injury. Utilizing a Transwell filter assay system and human umbilical vein SMCs, we sought to define the role of four different PA system components on SMC migration and matrix invasion: (1) PAs, (2) plasmin, (3) PA receptors, and (4) PA clearance receptors (ie, low density lipoprotein receptor-related protein [LRP]). Addition of active two-chain urokinase-type PA (UPA) stimulated random migration (192 +/- 30% of control, 0.36 nmol/L, P < .001). The stimulation was inhibited by pretreatment with diisopropylfluorophosphate, PA inhibitor type 1 (PAI-1), or aprotinin, a plasmin inhibitor. Augmented migration was also observed with either low-molecular-weight UPA or the amino terminal fragment of UPA (ATF), with the effects being additive. Stimulation by ATF alone, however, was not inhibited by aprotinin. The stimulatory effect was not specific for UPA, in that tissue-type PA (TPA) also increased migration (169 +/- 9% of control, 10 nmol/L, P < .001); the augmentation was inhibited by pretreatment with DFP, PAI-1, or aprotinin and was additive to the UPA effect. Antibodies to the UPA receptor but not 5'-nucleotidase (another glycosylphosphatidylinositol-anchored cell surface protein) inhibited baseline and UPA-stimulated migration. Similarly, both UPA and TPA stimulated invasion of a collagen gel; this augmentation was inhibited by aprotinin, whereas antibodies to the UPA receptor reduced baseline invasion. Finally, we tested whether inhibition of LRP function, which mediates internalization of PA/inhibitor complexes, affected either process. Both antibodies to LRP and recombinant receptor associated protein, a known inhibitor of ligand binding to the LRP, significantly inhibited migration but did not affect collagen gel invasion. These data demonstrate the ability of several components of the PA system to modulate SMC migration and invasion in vitro via plasmin-dependent and -independent mechanisms.
 ...
PMID:Contrasting effects of plasminogen activators, urokinase receptor, and LDL receptor-related protein on smooth muscle cell migration and invasion. 885 24

Migration of neutrophils in patients with paroxysmal nocturnal haemoglobinuria (PNH) was studied using two different complement-free in vitro model systems, subagarose and transendothelial migration. In the subagarose migration assay the mean migration distance of PNH neutrophils was slightly, but significantly, reduced to 1236 microns (range 753-1586, n = 6) compared to a normal mean of 1476 microns (range 1076-1768, n = 6, P = 0.016). By immunocytochemical staining for the urokinase type plasminogen activator receptor (uPAR) which is a glycosyl-phosphatidyl-inositol (GPI) anchored protein expressed by normal, but not by PNH-affected, neutrophils, it was shown that the uPAR-positive subpopulation of normal neutrophils predominated among the faster migrating cells (60-80% normal cells at the front of migration) while uPAR-negative (i.e. PNH-affected neutrophils) were more numerous close to the application well (5-30% normal cells). When migration of neutrophils was tested across a monolayer of human umbilical vein endothelial cells (HUVEC) cultured on polycarbonate filters, there was a 3-4-fold impairment of the migration of the PNH-affected neutrophils both in the absence of stimulation and after stimulation with fMLP (P < 0.001 in both cases). After IL-1 stimulation of the endothelium the impairment was even more pronounced (8-fold difference, P < 0.001). When the endothelial cells were grown on collagen-coated filters the impairment of the migration of PNH neutrophils was less pronounced, but still significant after stimulation with fMLP and IL-1 (2-fold, P < 0.05 in both cases). These results demonstrate that there is a complement-independent impairment of migration of neutrophils from patients with PNH which may be related to their failure to express GPI-linked proteins involved in cell migration and/or adhesion such as the uPA receptor and the CD66b antigen.
 ...
PMID:Impaired migration in vitro of neutrophils from patients with paroxysmal nocturnal haemoglobinuria. 885 37

A pathogenetic role for fibrin deposition and platelet activation in the kidney is thought to play a role in the pathogenesis of acute renal failure (ARF). Thus, some fibrinolytic parameters and platelet function have been studied in 17 patients with ARF and compared to healthy volunteers and subjects with chronic renal failure (CRF). Since serotonin may participate in pathological processes resulting from platelet/vessel wall interactions, its level in the whole blood and plasma was also assayed. In ARF and CRF platelet aggregatory responses in both whole blood and in platelet rich plasma upon stimulation with various agonists (collagen, arachidonic acid, ADP, ristocetin) were lower than those obtained in healthy volunteers. Increased levels of lipoprotein (a), von Willebrand factor (vWF) and fibronectin were found in ARF relative to controls. Protein C activity was significantly lower in patients with ARF. Euglobulin clot lysis time was prolonged in ARF and CRF, reflecting a decreased overall fibrinolytic activity. Activity of tissue plasminogen activator (tPA) inhibitor (PAI) and PAI:Ag were higher in ARF, whereas tPA:Ag, urokinase, tPA/PAI complexes, thrombin-antithrombin complexes (TAT), plasmin-antiplasmin (PAP) complexes, fibrinogen, and F1+2 did not differ between ARF and controls. In CRF elevated levels of TAT, PAP, fibrinogen and prothrombin fragments F1+2 were found, whereas concentration of fibronectin was lowered when compared to controls. In both groups of renal failure patients increased levels of fibrin monomers and d-dimer were found relative to healthy volunteers. Whole blood serotonin was significantly lower, whereas plasma serotonin was significantly higher in patients with ARF and CRF relative to controls. Serotonin uptake and its release from platelets were markedly diminished in patients with ARF and CRF. Chronic renal failure exhibit a slightly different pattern of coagulopathies that acute renal failure.
 ...
PMID:Hemostasis, platelet function and serotonin in acute and chronic renal failure. 887 44

Abnormalities in lipid metabolism appear to play a pathogenic role in progressive renal disease. To elucidate the cellular and molecular basis of renal interstitial fibrosis in uninephrectomized rats with diet-induced hypercholesterolemia, we fed experimental rats with standard rat chow supplemented with 4% cholesterol and 1% cholic acid. Control rats were fed an isocaloric diet. Groups of 7 control and 7 experimental rats were killed after 4, 8, and 12 weeks. Hypercholesterolemic rats developed albuminuria; serum creatinine was elevated at 12 weeks. By 12 weeks numerous oil red O-positive cells were present throughout the interstitium and to a lesser extent in tubules. Total renal lipid-peroxidation products were significantly increased (172 +/- 15, 198 +/- 28, and 197 +/- 13 mmol malondialdehyde/kidney at 4, 8, and 12 weeks vs. 123 +/- 17, 144 +/- 6, and 125 +/- 10 mmol in controls). Immunostaining revealed oxidatively modified lipoproteins within tubular and interstitial cells. The interstitial disease was characterized by an interstitial infiltrate of monocytes. Significant increases were detected in renal cortical mRNA levels for monocyte chemoattractant protein-1 (MCP-1), osteopontin, and vascular cell adhesion molecule-1 (VCAM-1), associated with changes in the pattern of immunostaining for each encoded proteins. Total kidney collagen was significantly increased at 12 weeks (9.8 +/- 0.9 mg/kidney vs. 7.8 +/- 0.9 mg in controls). At 12 weeks there was a significant increase in interstitial immunostaining for collagen I, collagen III, collagen IV, fibronectin and tenascin. A significant threefold increase in renal cortical mRNA levels for transforming growth factor beta-1 (TGF-beta 1) at 4 and 12 weeks was associated with the appearance of TGF-beta 1-positive interstitial cells. Renal matrix protein mRNA levels were measured at 4, 8, and 12 weeks. The only statistically significant elevations were procollagen alpha 1(I) and procollagen alpha 1(III) at weeks 8 and 12. In contrast, renal cortical mRNA levels for the tissue inhibitor of metalloproteinases-1 (TIMP-1) were significantly increased at 4, 8 and 12 weeks (1.4 +/- 0.5, 2.7 +/- 0.9 and 2.7 +/- 1.4 arbitrary densitometric units, respectively, vs. 1.0 +/- 0.4, 1.0 +/- 0.5 and 1.0 +/- 0.4 units for controls), and urokinase-type plasminogen activator (muPA) mRNA levels were significantly decreased at 4, 8, and 12 weeks (0.4 +/- 0.1 arbitrary densitometric units for all three experimental groups vs. 1.0 +/- 0.4, 1.0 +/- 0.3, and 1.0 +/- 0.4 units for the control groups). In summary, rats with diet-induced hypercholesterolemia develop renal interstitial fibrosis over several weeks. Following the accumulation of lipids within tubulointerstitial cells, interstitial nephritis develops. The fibrotic phase is characterized by modest changes in matrix protein mRNA levels, up-regulated TIMP-1, and down-regulated muPA levels, suggesting that altered matrix degradation plays a role in the interstitial fibrogenesis in this model.
 ...
PMID:Interstitial inflammation and fibrosis in rats with diet-induced hypercholesterolemia. 888 71

Fragments of the matrix molecule fibronectin (FN) have been shown to modulate tissue remodeling activity by inducing matrix metalloproteinases (MMPs) in synovial fibroblasts. These molecules could contribute to the tissue degradation that occurs during periodontal disease if they also modulate the expression of proteinases in cells of the periodontal ligament (PDL). We tested the hypothesis that FN and specific FN fragments induce the expression of specific proteinases in PDL cells. Using substrate zymograms, reverse zymograms and Western immunoblots, we found that PDL cells constitutively express 72 kDa gelatinase, urokinase-type plasminogen activator (uPA) and at least three inhibitors whose molecular masses correspond to those of the tissue inhibitors of metalloproteinases (TIMPs). A fourth, previously uncharacterized, proteinase inhibitor of approximately 22 kDa was also observed in some cell isolates. PDL cells, when exposed to a 120 kDa proteolytic FN fragment containing the cell-binding domain, were induced to express collagenase and stromelysin and also demonstrated an increased secretion of the serine proteinase uPA. Expression of collagenase increased with increasing concentrations (0.001 microM-1 microM) of the 120 kDa FN fragment. This fragment also induced the expression of a 20 kDa inhibitor, but not of the higher-molecular-mass inhibitors, in PDL cells. The observed alterations in proteinases were associated specifically with the 120 kDa FN fragment, since similar responses were not seen when PDL cells were exposed to either a 60 kDa heparin-binding FN fragment or a 45 kDa collagen/gelatin-binding FN fragment. PDL cells exposed to intact FN did not express the proteinases induced by the 120 kDa fragment but did express 92 kDa gelatinase and the 20 kDa proteinase inhibitor. These data suggest that FN and specific FN fragments can differentially induce the expression of proteinases in PDL cells. Thus, functional regions of FN may modulate many of the functions of PDL cells that contribute to periodontal disease, wound healing and maintenance of extracellular matrix in periodontal tissues.
 ...
PMID:Fibronectin and fibronectin fragments modulate the expression of proteinases and proteinase inhibitors in human periodontal ligament cells. 889 25

We inoculated the KLE human endometrial cancer, MCF-7 and ZR-75 human breast cancer, and PC-3 human prostate cancer cells into three-dimensional type I collagen gel system that contained uniformy dispersed MG-63 osteoblast-like cells. Then, we analyzed the morphological evidence of osteoblasts reaction, local invasion around the inoculated cancer cells and expression of the cathepsin D and urokinase-type plasminogen activator (uPA) around the sites of inoculation using immunocytochemistry. The prostate cancer cells produced morphological evidence of blastic reaction presented as an increased number of MG-63 osteoblasts and increase density of type I collagen around the sites of inoculation with PC-3 cells. The inoculated MCF-7 and ZR-75 cells decreased the density of type I collagen and number of osteoblasts and invaded the collagen gel around the sites of inoculation. The KLE endometrial cancer cells and cell-free media produced no reaction at the inoculation sites suggestive of cancer cell-specific interactions with osteoblasts in this system. The expression of uPA was remarkably higher at the inoculation sites of PC-3 cells as compared with those of the other cancer cells. Cathepsin D expression was higher at the sites of inoculation with KLE, MCF-7 and PC-3 cancer cells. MG-63 osteoblasts contained relatively low expression of uPA and cathepsin D. We conclude that this collagen gel system is a useful model for studying the morphological evidence of local invasion and osteoblasts reaction produced in response to local growth of metastatic cancer cell in vitro.
 ...
PMID:Three-dimensional type I collagen gel system containing MG-63 osteoblasts-like cells as a model for studying local bone reaction caused by metastatic cancer cells. 891 85

Thrombospondin (TSP) is produced by glomerular mesangial cells and one of the extracellular matrix in the mesangium, whereas the physiological role of TSP in mesangial cells is poorly understood. In order to know whether TSP modulates mesangial cell functions, we investigated the effects of TSP on cell adhesion, proliferation, synthesis of extracellular matrix and serine proteinases in cultured human mesangial cells. The substratum of TSP inhibited cell attachment and spreading in a TSP-dose-dependent manner in mesangial cells. Soluble TSP (50 micrograms/ml) also caused the detachment of fully adherent mesangial cells, whereas TSP less than 10 micrograms/ml did not. [3H]-thymidine incorporation into mesangial cells was dose-dependently reduced by TSP. On the other hand, the production of both fibronectin and type IV collagen from mesangial cells was enhanced by TSP. The incubation of mesangial cells with TSP increased the secretion of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), while plasminogen activator inhibitor-type 1 (PAI-1) decreased. These observations indicate that TSP inhibits cell adhesion and proliferation in cultured human mesangial cells. It is also suggested that TSP influences the metabolism of mesangial matrix by modulating both synthesis and degradation of matrix components. Thus, TSP, may be an important mediator of mesangial cell functions in an autocrine fashion.
 ...
PMID:Thrombospondin modulates adhesion, proliferation and production of extracellular matrix in mesangial cells. 892 89

The coordinate induction of protease activities and cell migration is a principal feature of endothelial cells (ECs) invading the interstitial space in the initial step of angiogenesis. However, the molecular mechanisms of these events are not fully characterized. Ets-1 is a member of the ets gene family of transcription factors, which binds to the Ets binding motif in the cis-acting elements and regulates the expression of certain genes. Four typical angiogenic growth factors, aFGF, bFGF, VEGF, and EGF, induced the expression of ets-1 mRNA in either human umbilical vein endothelial cells (HUVECs), ECV-304 cells (immortalized HUVECs), or human omental microvascular endothelial cells (HOMECs). The expression of ets-1 reached its maximum at 2 hr after factor addition and then decreased to the basal level by 12 hr. For characterization of the role of Ets-1 in angiogenesis, ets-1 antisense and sense oligodeoxynucleotides (ODNs) were constructed. The ets-1 antisense ODN but not sense ODN efficiently blocked the synthesis of Ets-1 protein by human ECs in response to angiogenic growth factors. Moreover, the ets-1 antisense ODN but not sense ODN almost completely abolished the binding of endothelial cell extract to DNA containing the Ets binding motif. The expression of urokinase-type plasminogen activator and matrix metalloproteinase-1 and the migration of ECs in response to growth factors were significantly inhibited by ets-1 antisense ODN but not by sense ODN. Tube formation by HOMECs in type 1 collagen gel stimulated with EGF was abrogated by ets-1 antisense ODN. Finally, the expression of Ets-1 protein in ECs during angiogenesis in vivo was confirmed by an immunohistochemical analysis using a murine angiogenesis model. These results indicate that the induction of ets-1 mRNA is a mutual phenomenon in ECs stimulated with angiogenic growth factors. Ets-1 appears to play an important role in angiogenesis, regulating the expression of proteases and the migration of ECs.
 ...
PMID:Ets-1 regulates angiogenesis by inducing the expression of urokinase-type plasminogen activator and matrix metalloproteinase-1 and the migration of vascular endothelial cells. 895 1

Thrombus age as a determinant of lysis efficacy has rarely been investigated. We developed an in vitro model to study the lysis of collagen induced platelet-fibrin-thrombi of different ages. Histologically, the thrombi were similar to those found in coronary vessels of patients deceased from acute myocardial infarction or unstable angina. After 10 (TA10), 30(TA30) und 60 (TA60) min of thrombus aging thrombolysis over 30 min with urokinase alone or in combination with prostaglandin E1 was started. The efficacy of lysis with urokinase alone decreased with increasing thrombus age. After 30 min of lysis with urokinase alone weight of TA10-thrombi was reduced by 16.4 +/- 1.2 mg, of TA30-thrombi by 11.5 +/- 0.9 mg (p < 0.001 vs TA10-thrombi) and of TA60-thrombi by 7.8 +/- 1.1 mg (p < 0.001 vs TA30, p < 0.0001 vs TA10-thrombi). The addition of prostaglandin Ei augmented lysis of TA10-thrombi, after 30 min of lysis thrombus weight was reduced by 17.3 +/- 1.2 mg (p < 0.01 vs urokinase alone). Lysis of 30 and 60 min old thrombi was nearly unaffected. Thus, thrombus age is a strong predictor of lysis efficacy of in vitro collagen induced platelet-fibrin-thrombi.
 ...
PMID:[Thrombus age as a determinant of lysis efficacy of in vitro produced platelet-fibrin thrombi]. 899 9


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>