scholarly journals 4G/4G PAI-1 gene variant in a patient with non-healing ulcers

2015 ◽  
Vol 2 (1) ◽  
pp. 91
Author(s):  
Heather Peluso ◽  
Julie A. Caffrey ◽  
Stephen M. Milner
Keyword(s):  
Cell Migration ◽  
Plasminogen Activator ◽  
Traumatic Injury ◽  
Skin Grafting ◽  
Plasminogen Activator Inhibitor ◽  
Fibrin Clot ◽  
Serpin Gene ◽  
Homozygous Genotype ◽  
Minimal Trauma ◽  
Pai 1

Plasminogen activator inhibitor is a serine protease inhibitor from the serpin gene family that modulates fibrin clot breakdown.PAI-1 irreversibly inhibits tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA) from activatingplasminogen. PAI-1 also inhibits integrin-vitronectin and vitronectin-vitronectin interactions that are essential for cell migration,adhesion, and angiogenesis. We describe a patient, who developed chronic non-healing ulcers after minimal trauma to severalareas of his body. Genetic testing revealed the 4G/4G homozygous genotype for the polymorphism in the promoter regionof the PAI-1 gene. Increased PAI-1 activity prevents the breakdown of the fibrin clot and cell migration to remodel damagedtissue. A combination of poor clot fibrinolysis and cell recruitment to the site of injury may explain our patient’s non-healingulcers following minor traumatic injury. Early treatment with excision and skin grafting may benefit patients presenting withnon-healing ulcers and the homozygous 4G/4G PAI-1 variant. To our knowledge, there have been no reports in the literatureassociating PAI-1 overexpression and chronic non-healing wounds.

The Roles of α2-Antiplasmin and Plasminogen Activator Inhibitor 1 (PAI-1) in the Inhibition of Clot Lysis

1993 ◽  
Vol 70 (02) ◽  
pp. 301-306 ◽  
Author(s):  
Linda A Robbie ◽  
Nuala A Booth ◽  
Alison M Croll ◽  
Bruce Bennett
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Fibrin Clot ◽  
Clot Lysis ◽  
Plasminogen Activator Inhibitor 1 ◽  
Dependent Inhibition ◽  
Activator Inhibitor ◽  
Pai 1

SummaryThe relative importance of the two major inhibitors of fibrinolysis, α2-antiplasmin (α2-AP) and plasminogen activator inhibitor (PAI-1), were investigated using a simple microtitre plate system to study fibrin clot lysis in vitro. Cross-linked fibrin clots contained plasminogen and tissue plasminogen activator (t-PA) at concentrations close to physiological. Purified α2-AP and PAI-1 caused dose-dependent inhibition. All the inhibition due to normal plasma, either platelet-rich or poor, was neutralised only by antibodies to α2-AP. Isolated platelets, at a final concentration similar to that in blood, 2.5 × 108/ml, markedly inhibited clot lysis. This inhibition was neutralised only by antibodies to PAI-1. At the normal circulating ratio of plasma to platelets, α2-AP was the dominant inhibitor. When the platelet:plasma ratio was raised some 20-fold, platelet PAI-1 provided a significant contribution. High local concentrations of PAI-1 do occur in thrombi in vivo, indicating a role for PAI-1, complementary to that of α2-AP, in such situations.

Abstract 188: Selective Inhibition of Vascular Smooth Muscle Cell Migration by Targeting Plasminogen Activator Inhibitor-1

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Neha Goyal ◽  
Zhen Weng ◽  
Philip Fish ◽  
Tammy Strawn ◽  
Samantha Myears ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cell Migration ◽  
Plasminogen Activator ◽  
Intimal Hyperplasia ◽  
Differential Effect ◽  
Plasminogen Activator Inhibitor ◽  
Dependent Manner ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

Introduction: Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of mammalian plasminogen activators and an important regulator of cell migration. We have shown that tiplaxtinin, a small molecule, specific inhibitor of PAI-1, inhibits intimal hyperplasia in a murine vein graft model. However, little is known about the effects of pharmacological inhibition of PAI-1 on vascular cell migration under physiologically relevant conditions. Methods: We studied the effects of tiplaxtinin on migration of smooth muscle cells (SMCs) and endothelial cells (ECs). Results: Tiplaxtinin significantly inhibited migration of murine SMCs through 3-dimensional (3-D) collagen matrix in a concentration-dependent manner. Tiplaxtinin did not inhibit SMC proliferation, and it did not inhibit migration of PAI-1-deficient SMCs, suggesting that tiplaxtinin’s effect on SMCs was non-toxic and PAI-1-dependent. The anti-migratory effect of tiplaxtinin on SMCs was preserved in collagen 3-D matrix containing vitronectin and other extracellular matrix molecules, further supporting the physiological significance of the effect. In contrast to SMCs, tiplaxtinin did not inhibit migration of human aortic ECs in vitro or murine ECs in vivo, the latter assessed in a murine carotid injury model. To study the basis for the differential effect of tiplaxtinin on SMCs vs. ECs, we compared expression of LDL receptor-related protein 1 (LRP1), a motogenic receptor for PAI-1, between cell types by RT-PCR and found that LRP1 gene expression was significantly lower in ECs than in SMCs. Furthermore, recombinant PAI-1 stimulated the migration of wild-type mouse embryonic fibroblasts (MEFs), but not LRP1-deficient MEFs. Conclusions: Tiplaxtinin, a pharmacological inhibitor of PAI-1, inhibits SMC migration under physiological conditions, while having no inhibitory effect on EC migration. The differential effect of PAI-1 inhibition on SMCs vs. ECs appears to be mediated by LRP1 and may be of clinical significance, as it is advantageous to prevent intimal hyperplasia by inhibiting SMC migration without inhibiting EC migration, which is key to preserving an intact, anti-thrombotic vascular endothelium.

scholarly journals Expression of plasminogen activator-inhibitor-1 (PAI-1) during cellular remodeling in proliferative glomerulonephritis in the rat.

1995 ◽  
Vol 43 (9) ◽  
pp. 895-905 ◽  
Author(s):  
J L Barnes ◽  
R J Mitchell ◽  
E S Torres
Keyword(s):  
Extracellular Matrix ◽  
Cell Migration ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Proliferative Glomerulonephritis ◽  
Plasminogen Activator Inhibitor 1 ◽  
Glomerular Lesions ◽  
Matrix Accumulation ◽  
Activator Inhibitor ◽  
Pai 1

Pericellular proteolysis involves the plasminogen activator/plasmin system and plays an important role in cell remodeling involving cell migration and extracellular matrix turnover. Studies in this laboratory have previously characterized a model of proliferative glomerulonephritis induced by Habu snake venom (HSV) in the rat that involves cell migration, proliferation, and extracellular matrix accumulation. Because plasminogen activator-inhibitor-1 (PAI-1) has been used as a marker for cell migration as well as matrix accumulation, we were interested in examining the temporal and spatial expression and cellular sources of PAI-1 mRNA and translated protein over the course of HSV-induced proliferative glomerulonephritis. The results showed a highly localized and progressive expression of PAI-1 mRNA and translated protein by in situ hybridization and immunohistochemistry at the margins and periphery of glomerular lesions 8 and 24 hr after HSV. The expression of PAI-1 in glomerular lesions localized to the same sites as mesangial cell marker proteins, desmin and Thy-1.1, indicating that mesangial cells synthesize this important regulator proteolysis. Few cells expressed PAI-1 in the central aspects of glomerular lesions at later time intervals (48 and 72 hr) when cell proliferation and expression of extracellular matrix (fibronectin protein and mRNA) were maximal. Therefore, the expression of PAI-1 in this model was associated more with early events related to cell migration than with proliferation or extracellular matrix synthesis. These observations support the hypothesis that the plasminogen activator/plasmin system is involved in cell migration in early remodeling during glomerular disease.

scholarly journals Gastrin stimulates expression of plasminogen activator inhibitor-1 in gastric epithelial cells

2011 ◽  
Vol 301 (3) ◽  
pp. G446-G453 ◽  
Author(s):  
Kristin G. Nørsett ◽  
Islay Steele ◽  
Cedric Duval ◽  
Stephen J. Sammut ◽  
Senthil V. M. Murugesan ◽  
...  
Keyword(s):  
Cell Migration ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Migration And Invasion ◽  
Luciferase Expression ◽  
Elevated Plasma ◽  
Plasma Gastrin ◽  
Cell Migration And Invasion ◽  
Activator Inhibitor ◽  
Pai 1

Plasminogen activator inhibitor (PAI)-1 is associated with cancer progression, fibrosis and thrombosis. It is expressed in the stomach but the mechanisms controlling its expression there, and its biological role, are uncertain. We sought to define the role of gastrin in regulating PAI-1 expression and to determine the relevance for gastrin-stimulated cell migration and invasion. In gastric biopsies from subjects with elevated plasma gastrin, the abundances of PAI-1, urokinase plasminogen activator (uPA), and uPA receptor (uPAR) mRNAs measured by quantitative PCR were increased compared with subjects with plasma concentrations in the reference range. In patients with hypergastrinemia due to autoimmune chronic atrophic gastritis, there was increased abundance of PAI-1, uPA, and uPAR mRNAs that was reduced by octreotide or antrectomy. Immunohistochemistry revealed localization of PAI-1 to parietal cells and enterochromaffin-like cells in micronodular neuroendocrine tumors in hypergastrinemic subjects. Transcriptional mechanisms were studied by using a PAI-1-luciferase promoter-reporter construct transfected into AGS-GR cells. There was time- and concentration-dependent increase of PAI-1-luciferase expression in response to gastrin that was reversed by inhibitors of the PKC and MAPK pathways. In Boyden chamber assays, recombinant PAI-1 inhibited gastrin-stimulated AGS-GR cell migration and invasion, and small interfering RNA treatment increased responses to gastrin. We conclude that elevated plasma gastrin concentrations are associated with increased expression of gastric PAI-1, which may act to restrain gastrin-stimulated cell migration and invasion.

Effect of Plasminogen Activator Inhibitor-1 on Tissue-Type Plasminogen Activator-Induced Fibrinolysis

1992 ◽  
Vol 67 (01) ◽  
pp. 106-110 ◽  
Author(s):  
Marcus E Carr ◽  
C Krishnamurti ◽  
B M Alving
Keyword(s):  
Plasminogen Activator ◽  
Degradation Products ◽  
Plasminogen Activator Inhibitor ◽  
Fibrin Clot ◽  
Tissue Type ◽  
Single Chain ◽  
Plasminogen Activator Inhibitor 1 ◽  
Human Thrombin ◽  
Activator Inhibitor ◽  
Pai 1

SummaryThe effect of fibrin on the interaction of human recombinant single-chain tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) was studied in normal rabbit plasma and in plasma with high levels of native PAI-1. t-PA was added to diluted plasma containing calcium (10 mM) and 125I-fibrinogen at 37° C. Clotting was initiated with human thrombin, and lysis was monitored both turbidimetrically and by release of 125I-fibrin degradation products (fdp). The activity of t-PA (50 IU/ml) was rapidly reduced to 15% of the initial value in plasma containing PAI-1 (23 AU/ml). When thrombin and t-PA were added simultaneously to the plasma, more than 70% of the activity was retained through incorporation of t-PA into the fibrin clot. t-PA-induced fibrinolysis in PAI-1 enriched plasma was further delayed when the temperature was reduced from 37 to 25° C. Turbidimet-ric and 125I-fdp release data provided complementary information. The former technique traced fiber dissolution, while the latter reflected network integrity. These results indicate that t-PA-induced fibrinolysis in PAI-1 enriched plasma is modulated by the presence of fibrin and by temperature.

Hesperetin and its sulfate and glucuronide metabolites inhibit TNF-α induced human aortic endothelial cell migration and decrease plasminogen activator inhibitor-1 (PAI-1) levels

2016 ◽  
Vol 7 (1) ◽  
pp. 118-126 ◽  
Author(s):  
Juan Antonio Giménez-Bastida ◽  
Antonio González-Sarrías ◽  
Fernando Vallejo ◽  
Juan Carlos Espín ◽  
Francisco A. Tomás-Barberán
Keyword(s):  
Cell Migration ◽  
Endothelial Cell ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Endothelial Cell Migration ◽  
Human Aortic Endothelial Cell ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tnf Α ◽  
Activator Inhibitor ◽  
Pai 1

Hesperetin and its derived metabolites, at physiologically relevant concentrations, significantly attenuated TNF-α-induced cell migration.

scholarly journals The viral accelerated NF-κB pathway drives COVID-19-associated coagulopathy via excessive transcription of tissue factor and plasminogen activator inhibitor 1 – case report

2021 ◽  
Author(s):  
Marco Leitzke ◽  
Joao-Carlos Correia ◽  
Peter Oskar Dieter Schönknecht
Keyword(s):  
Tissue Factor ◽  
Plasminogen Activator ◽  
Rare Complication ◽  
Plasminogen Activator Inhibitor ◽  
Fibrin Clot ◽  
Thromboembolic Complications ◽  
Plasminogen Activator Inhibitor 1 ◽  
New Evidence ◽  
Activator Inhibitor ◽  
Pai 1

Abstract The current COVID-19 pandemic creates new clinical challenges almost daily, especially in terms of individual prognoses, diagnostics involving newly discovered pathogenic mechanisms, and the appearance of SARS-CoV-2 mutations. In terms of the thromboembolic complications frequently occurring in COVID-19 patients, there is new evidence that pathognomonic COVID-19-associated coagulopathy (CAC) differs considerably from the coagulant malfunction of common disseminated intravascular coagulation. Thus, bleeding is a rare complication in the initial stages of the disease, whereas thrombotic formations can be seen autopticly in the vasculature of several organs. Therefore, it is speculated that most thromboembolic complications are thrombotic rather than embolic, and CAC is more likely to be a pro-coagulant form of coagulopathy. The reasons for these key differences have remained unknown until very recently. The relationship between SARS-CoV-2 infection and the virus-related acceleration of the transcriptional nuclear factor kappa B (NF-κB)-pathway, with the accompanied excessive downstream release of NF-κB-dependent proteins, is undisputed. Therefore, the roles of the NF-κB-transcribed anti-fibrinolytic plasminogen activator inhibitor (PAI 1) and NF-κB-dependent tissue factor (TF) have become worthy of attention. Inappropriate TF action results in enhanced fibrin clot formation, whereas overexpression of PAI 1 prevents appropriate fibrinolytic reactions. CAC is interpreted as critically contributing to overall COVID-19 pathology and is most likely an independent risk factor for mortality.

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