Leukocyte urokinase plasminogen activator receptor and PSGL1 play a role in endogenous arterial fibrinolysis

2009 ◽  
Vol 102 (12) ◽  
pp. 1212-1218 ◽  
Author(s):  
Xufang Bai ◽  
Jeffrey Weitz ◽  
Peter Gross
Keyword(s):  
Plasminogen Activator ◽  
High Speed ◽  
Wild Type ◽  
Urokinase Plasminogen Activator Receptor ◽  
Activated Platelets ◽  
Upa Receptor ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Plasminogen Activator Receptor ◽  
Deficient Mice

SummaryFibrin is an integral component of arterial thrombi. Using a mouse model of arteriolar thrombosis, high-speed fluorescence microscopy reveals that, within minutes, the fibrin content of thrombi rapidly increases and then decreases.The decrease in fibrin coincides with leukocyte binding to the thrombi, a process mediated by the interaction of leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) with P-selectin on the surface of activated platelets. Because leukocytes possess urokinase-type plasminogen activator (uPA) activity,we used mice deficient in uPA or the uPA receptor (uPAR) to explore the contribution of leukocyte associated uPA to the loss of fibrin from these thrombi. Fibrin loss in both uPA-deficient mice and uPAR-deficient mice was reduced compared with that in wild-type controls.Transfusion of leukocytes from wild-type mice into uPAR-deficient mice restored fibrin loss to levels similar to that in wild-type mice. In contrast, transfusion of leukocytes from mice deficient in uPAR or PSGL-1 did not enhance fibrin loss. Thus, fibrin loss from microarteriolar thrombi is mediated, at least in part, by leukocyte-associated uPA in a process that requires leukocyte uPAR and PSGL-1.

Endogenous Arteriolar Fibrinolysis Requires Urokinase Plasminogen Activator and Leukocyte Urokinase Plasminogen Activator Receptor-1.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 545-545
Author(s):  
Xufang Bai ◽  
Peter L. Gross
Keyword(s):  
Plasminogen Activator ◽  
High Speed ◽  
Thrombus Formation ◽  
Urokinase Plasminogen Activator ◽  
Wild Type ◽  
Plasmin Activity ◽  
Urokinase Plasminogen Activator Receptor ◽  
Upa Receptor ◽  
Deficient Mice ◽  
Endogenous Fibrinolysis

Abstract Background: In venous thrombi, urokinase associated with leukocytes activates plasminogen to initiate endogenous fibrinolysis. Leukocytes also interact with arteriolar thrombi. Objectives: We hypothesized that urokinase plasminogen activator (uPA) activity would also be delivered to arteriolar thrombi by leukocytes. Methods: Using established techniques of high-speed intravital fluorescence microscopy to observe the cremaster muscle of mice, we measured platelet and fibrin accumulation in thrombi generated by a laser injury to arterioles. The accumulation of platelets in a thrombus is quantitated by measuring the fluorescence from anti-CD41 antibody tagged with a fluorescent secondary antibody and the presence of fibrin is detected using a fluorescence-tagged anti-fibrin antibody (T2G1). Results: In C57BL/6 wild type mice, fibrin increased to a maximum at about three minutes after thrombus formation and then decreased, such that by eight minutes after thrombus formation fibrin is present at 34% of its maximal value. When wild type mice are pretreated with epsilon-aminocaproic acid (16 mg/kg IV), the decrease in thrombus fibrin content was less (to 54% of maximal 8 minutes after thrombus formation), implying that the fibrin loss is at least partially the result of plasmin activity. Thrombus fibrin accumulation in tissue-plasminogen activator deficient mice (Plat) was greater, peaking at 229% the amount found in wild type mice, but the amount of fibrin present at eight minutes after thrombus formation was not dissimilar from wild type mice (45% ± 5% v. 34% ± 3%, P=0.09). In uPA-deficient mice (Plau) and uPA-receptor-1-deficient mice (Plaur), the amount of maximal thrombus fibrin was 189% and 273% that of fibrin content in wild type mice. Also, although thrombus fibrin did decrease over time in Plau and Plaur mice, it decreased to only 51% and 48% of maximal (each were P < 0.005 v. wild type) at eight minutes after thrombus formation. When wild type leukocytes, isolated from blood by differential centrifugation and sucrose density gradient, were transfused into Plaur mice, thrombus fibrin loss was restored to wild type levels (38% of maximal at 8 minutes after thrombus formation, P=0.36 vs. wild type, P=0.016 vs. Plaur), implying that transfused wild type leukocytes, which express uPA-receptor-1, can rescue fibrinolysis in uPA-receptor-1-deficient mice. Conclusions: These results confirm that endogenous fibrinolytic activity in vivo occurs soon after arteriolar thrombus formation. The plasminogen activators that are required for this fibrinolysis to occur are uPA, and the uPA-receptor-1 on leukocytes. These findings are compatible with the hypothesis that leukocytes can deliver plasminogen activator activity to arteriolar thrombi to initiate endogenous fibrinolysis.

Urokinase-type plasminogen activator receptor is associated with the development of adipose tissue

2010 ◽  
Vol 104 (12) ◽  
pp. 1124-1132 ◽  
Author(s):  
Hiroyuki Matsuno ◽  
Eri Kawashita ◽  
Kiyotaka Okada ◽  
Hidetaka Suga ◽  
Shigeru Ueshima ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Plasminogen Activator ◽  
Adipocyte Differentiation ◽  
Cellular Adhesion ◽  
Wild Type ◽  
Tissue Mass ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Plasminogen Activator Receptor

SummaryUrokinase-type plasminogen activator receptor (uPAR) plays a role in cellular responses which include cellular adhesion, differentiation, proliferation and migration. The aim of this study was to clarify the role of uPAR on the development of adipose tissue. To clarify the role of uPAR on adipogenesis, we examined the effect of uPAR overexpression and uPAR deficiency on the adipocyte differentiation. Adipocyte differentiation was induced by incubation of 3T3-L1 cells with differentiation media containing insulin, dexamethasone, and 1-methyl-3-isobutylxanthin. uPAR overexpression by transfection of uPAR expression vector induced adipocyte differentiation. In addition, we examined the difference in adipocyte differentiation of mesenchymal stem cells from wild-type mice and uPAR knockout (uPAR-/-) mice. The uPAR deficiency attenuated differentiation media-induced adipocyte differentiation. Moreover, we found that the inhibition of phosphatidylinositol 3-kinase (PI3K) pathway attenuated uPAR overexpression-induced adipocyte differentiation, and uPAR overexpression induced the activation of Akt. We also found that an increase of the adipose tissue mass in uPAR-/- mice was less than that observed in wild-type mice. The present results suggest that uPAR plays a pivotal role in the development of adipose tissue through PI3K/Akt pathway.

scholarly journals Antigen levels of urokinase-type plasminogen activator receptor and its gene polymorphism related to microvessel density in colorectal cancer.

2008 ◽  
Vol 55 (2) ◽  
pp. 357-363
Author(s):  
Karolina Przybylowska ◽  
Janusz Szemraj ◽  
Andrzej Kulig ◽  
Adam Dziki ◽  
Joanna Ulanska ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Plasminogen Activator ◽  
Microvessel Density ◽  
Repeat Polymorphism ◽  
Urokinase Plasminogen Activator Receptor ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Its Gene ◽  
Plasminogen Activator Receptor ◽  
Colorectal Cancer Patients

We determined the distribution of genotypes and frequencies of alleles of the (CA)(n) repeat polymorphism in intron 3 of the urokinase plasminogen activator receptor (uPAR) gene, uPAR antigen levels and microvessel density (MVD) in tumour and distant mucosa samples from 52 patients with colorectal cancer. The uPAR level was higher for patients with high MVD comparing to patients with lower MVD which may suggest that uPAR can be correlated with progression of colorectal cancer. The significant relationship between the high MVD and uPAR antigen level appeared to be independent of the (CA)(n) repeat polymorphism because no differences in the level of uPAR antigen between carriers of alleles were found. The received results, indicate that uPAR might be considered as a target in colorectal cancer patients' therapy.

Liver regeneration is transiently impaired in urokinase-deficient mice

1998 ◽  
Vol 275 (6) ◽  
pp. G1472-G1479 ◽  
Author(s):  
Heather T. Roselli ◽  
Ming Su ◽  
Kay Washington ◽  
David M. Kerins ◽  
Douglas E. Vaughan ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Thymidine Incorporation ◽  
Fibrin Deposition ◽  
Wild Type ◽  
Upa Receptor ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Deficient Mice

To test the hypothesis that urokinase-type plasminogen activator (uPA) plays an important role in liver regeneration in vivo, partial hepatectomy was performed on wild-type and uPA-deficient (uPA−/−) mice. Mice were studied at 24, 44, and 96 h and at 8 days and 4 wk post-partial hepatectomy for evidence of regeneration, as measured by mitotic indexes and [3H]thymidine incorporation. In wild-type mice, thymidine incorporation peaked at 44 h and this index was reduced by 47% in uPA−/− mice ( P= 0.02). By 8 days, however, liver mass was comparable in both groups. Histological analysis revealed the presence of focal areas of fibrin deposition and cellular loss by 24 h that were more severe and prevalent in uPA−/− mice than in wild-type mice (62 and 23%, respectively; χ2 = 3.939, P = 0.047). In contrast, regeneration was not impaired in uPA receptor (uPAR)-deficient mice at 24 and 44 h. Taken together, these data indicate that uPA, independent of its interaction with the uPAR, plays an important role in liver regeneration in vivo.

The urokinase-type plasminogen activator receptor is not required for skeletal muscle inflammation or regeneration

2007 ◽  
Vol 293 (3) ◽  
pp. R1152-R1158 ◽  
Author(s):  
Scott C. Bryer ◽  
Timothy J. Koh
Keyword(s):  
Skeletal Muscle ◽  
Plasminogen Activator ◽  
Muscle Regeneration ◽  
Inflammatory Cells ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Plasminogen Activator Receptor

The hypothesis of this study was the urokinase-type plasminogen activator receptor (uPAR) is required for accumulation of inflammatory cells in injured skeletal muscle and for efficient muscle regeneration. Expression of uPAR was elevated at 1 and 3 days after cardiotoxin-induced muscle injury in wild-type mice before returning to baseline levels. Neutrophil accumulation peaked 1 day postinjury in muscle from both wild-type (WT) and uPAR null mice, while macrophage accumulation peaked between 3 and 5 days postinjury, with no differences between strains. Histological analyses confirmed efficient muscle regeneration in both wild-type and uPAR null mice, with no difference between strains in the formation or growth of regenerating fibers, or recovery of normal morphology. Furthermore, in vitro experiments demonstrated that chemotaxis is not different between WT and uPAR null macrophages. Finally, fusion of cultured satellite cells into multinucleated myotubes was not different between cells isolated from WT and uPAR null mice. These results demonstrate that uPAR is not required for the accumulation of inflammatory cells or the regeneration of skeletal muscle following injury, suggesting uPA can act independently of uPAR to regulate events critical for muscle regeneration.

Metalloproteases Cleave the Urokinase-Type Plasminogen Activator Receptor in the D1-D2 Linker Region and Expose Epitopes not Present in the intact Soluble Receptor

2002 ◽  
Vol 88 (08) ◽  
pp. 298-306 ◽  
Author(s):  
Annapaola Andolfo ◽  
William English ◽  
Massimo Resnati ◽  
Gillian Murphy ◽  
Francesco Blasi ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Vascular Endothelial Cells ◽  
Peptide Bond ◽  
Feedback Mechanism ◽  
Biologically Active ◽  
Urokinase Plasminogen Activator Receptor ◽  
Linker Region ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Plasminogen Activator Receptor

SummaryProteolytic cleavage of the urokinase plasminogen activator receptor (uPA(R)) prevents the binding of uPA and vitronectin while generating biologically active uPAR fragments. We have recently shown that matrix metalloproteinase-12 (MMP-12) releases cellular uPAR-antigen from stimulated human micro-vascular endothelial cells providing a novel feedback mechanism between the plasminogen activation and MMP systems. We now show that MMP-12 and other MMPs directly and efficiently cleave uPAR at the Thr86||Tyr87 peptide bond located in the linker region connecting uPAR domains 1 and 2, releasing the major ligand binding domain 1 from the rest of the receptor. The possible biological importance of uPAR cleavage by MMPs is supported by the observation that also murine uPAR is cleaved by MMP-12 (at the Pro89||Gln90 peptide bond), despite the limited sequence homology between the linker regions. Using an antibody raised against the human uPAR linker region we show that this region of uPAR, which contains the chemotactic SRSRY epitope, is exposed upon MMP cleavage.

scholarly journals Urokinase and its receptor uPAR is a critical component of pulmonary renal cascade and is significant for pulmonary function and contributes to the physiological regulation; relationship with Serpin E2

2019 ◽  
Vol 8 (3) ◽  
Author(s):  
Manoj G Tyagi ◽  
Vikram GS ◽  
Vishakha Tyagi ◽  
Dharmendra Singh ◽  
S Thirumalai Velu
Keyword(s):  
Pulmonary Function ◽  
Plasminogen Activator ◽  
Soluble Form ◽  
Urokinase Plasminogen Activator Receptor ◽  
Physiological Regulation ◽  
Upa Receptor ◽  
Type Plasminogen Activator ◽  
Plasminogen Activator Receptor ◽  
Lung Endothelial Cells ◽  
Protease Nexin

Many previous studies have shown that induction of uPA, uPA receptor (uPAR), and PAI-1 may occur in lung endothelial cells (ECs) through a uPA-mediated feedback pathway. Soluble urokinase-type plasminogen activator receptor (suPAR) is a soluble form of the urokinase plasminogen activator receptor (uPAR) that is produced upon cleavage of membrane-bound uPAR. It is found in various body fluids, including blood, urine and cerebrospinal fluid. It is now known that Pulmonary function in physiological and patho-physiological condition is regulated by these molecules. On the other hand, Protease nexin-1 or serine protease inhibitor (Serpin E2) is intricately linked in the physiological homeostasis and interacts with uPA system. These are the key elements of the pulmonary renal cascade regulating multiple physiological functions. Key words: Urokinase, suPAR, lungs, SERPIN, physiological, airways

Mice Deficient in Urokinase-Type Plasminogen Activator (uPA) or uPA Receptor Develop Significantly Diminished Collagen-Induced Arthritis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 580-580
Author(s):  
Sherry Thornton ◽  
Harini Raghu ◽  
Alice Jone ◽  
Carolina Cruz ◽  
Cheryl L. Rewerts ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasminogen Activator ◽  
Joint Disease ◽  
Inflammatory Joint Disease ◽  
Collagen Induced Arthritis ◽  
Disease Pathogenesis ◽  
Upa Receptor ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Deficient Mice

Abstract Rheumatoid arthritis (RA) is a common and debilitating autoimmune disease characterized by chronic inflammation, synovial hyperplasia, edema, cartilage and bone erosion and loss of joint function. Increasing evidence suggests that the plasminogen activation (PA) system plays a fundamental role in the mechanisms mediating inflammatory joint disease pathogenesis. However, analysis of the precise contribution of PA system components to arthritis pathogenesis has been complicated by the use of gene-targeted mice on non-susceptible genetic backgrounds or experimental models that simultaneously induce wound trauma in conjunction with arthritis induction. To rigorously define the contribution of the urokinase-type plasminogen activator system to arthritis pathogenesis, previously generated genetic deficiencies in both uPA and uPA receptor (uPAR) were inbred for 7 generations (99% inbred) to the well-characterized, collagen-induced arthritis (CIA)-susceptible strain, DBA/1J. Our results indicate a near complete amelioration of joint disease in uPA-deficient mice that was also observed in uPAR-deficient mice. Limited disease development in both uPA- and uPAR-deficient mice correlated with significantly reduced local mRNA levels of key inflammatory mediators (e.g., TNFα, IL-1β, and IL-6) in these animals. To determine if development of inflammatory joint disease in CIA-challenged mice was dependent on the expression of uPAR by non-hematopoietic- or hematopoietic-derived cells, reciprocal bone marrow transplant studies were performed. Mice in which uPAR deficiency was limited to the bone marrow compartment elicited significantly reduced macroscopic and histopathological disease in the paws and knees compared to wild-type mice or mice in which only hematopoietic-derived cells express uPAR. Our results are the first to report in the context of the highly CIA susceptible DBA/1 background that both uPA and uPAR are key determinants of inflammatory joint disease pathogenesis. Furthermore, our findings indicate a fundamental role for uPAR expression by hematopoietic cells in driving arthritis incidence and progression. Thus, these findings suggest that cell-surface associated uPA/uPAR-mediated proteolysis and/or uPAR-mediated signaling events from bone-marrow derived cells are important in promoting inflammatory joint disease, and that disrupting this key proteolytic/signaling system may provide a novel therapeutic strategy to limit clinical arthritis. Disclosures No relevant conflicts of interest to declare.

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