Plasminogen Activator Inhibitor 1 Deficiency Reduces the Progression of Atherosclerosis in a Murine Model of Human Familial Hypercholesterolemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1804-1804
Author(s):  
Takayuki Iwaki ◽  
Ploplis A. Victoria ◽  
Francis J. Castellino
Keyword(s):  
Plasminogen Activator Inhibitor ◽  
Cell Types ◽  
Cellular Functions ◽  
Plasminogen Activator Inhibitor 1 ◽  
Aortic Sinus ◽  
Atherosclerosis Progression ◽  
Plaque Area ◽  
And Migration ◽  
Progression Of Atherosclerosis ◽  
Pai 1

Abstract Atherosclerosis has been described as a “self-perpetuating” inflammatory disease which progresses in discrete stages and involves a number of cell types and effector molecules. Lipid metabolic disorders are heavily involved in the genesis and progression of atherosclerosis in humans, and thrombotic complications substantially contribute to the coronary artery disease that frequently accompanies atherosclerosis. A relevant mouse model of human atherosclerosis with elevated LDL-cholesterol (C) is one in which both the Ldlr and Apobec1 genes are deleted (Ldlr−/−/Apobec1−/−), since these mice lack the ability to convert apoB-100 to apoB-48 in liver and also are defective in LDL clearance. We have generated Ldlr−/−/Apobec1−/−/PAI-1−/−and characterized atherosclerosis progression in these mice. VLDL, LDL, HDL, and total C levels were identical between Ldlr−/−/Apobec1−/−and Ldlr−/−/Apobec1−/−/PAI-1−/−mice (VLDL-C; 30.3±1.8 vs 26.0±1.7 (mg/dl), LDL-C; 268.7±6.3 vs 274.1±13.1 (mg/dl), HDL-C; Total-C; 353.8±8.1 vs 356.8±14.5 (mg/dl), respectively). However, both the plaque size in the aortic sinus and the extent of plaque area in aorta were significantly smaller in Ldlr−/−/Apobec1−/−/PAI-1−/−mice relative to Ldlr−/−/Apobec1−/−mice (plaque in aortic sinus; 158792.9±11958.2 vs 227243.5±15291.1 (μm2), plaque area in aorta; 3.90±0.34 vs 5.10±0.27 (%), respectively). To elucidate the cellular functions, especially macrophages, in the plaque, bone marrow-derived macrophages (BMMs) were isolated and utilized for Dil-oxidized (Ox) LDL uptake assays and migration assays using 8 μm pore culture inserts. There were no significant differences in Dil-OxLDL uptake by BMMs between the two genotypes. The kinetics of migration of BMMs was more rapid in Ldlr−/−/Apobec1−/−/PAI-1−/−cells than Ldlr−/−/Apobec1−/−cells. Furthermore, thioglycollate-induced intraperitoneal migration of macrophages was increased in Ldlr−/−/Apobec1−/−/PAI-1−/−mice vs Ldlr−/−/Apobec1−/−mice. Results from these studies indicate that cell migratory differences may contribute to attenuating atheroma formation in a PAI-1 deficient state.

Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4212-4215 ◽  
Author(s):  
Daniel T. Eitzman ◽  
Randal J. Westrick ◽  
Zuojun Xu ◽  
Julia Tyson ◽  
David Ginsburg
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Carotid Bifurcation ◽  
Plasminogen Activation ◽  
Plasminogen Activator Inhibitor 1 ◽  
Atherosclerosis Progression ◽  
Plasminogen Activation System ◽  
Activation System ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Dissolution of the fibrin blood clot is regulated in large part by plasminogen activator inhibitor-1 (PAI-1). Elevated levels of plasma PAI-1 may be an important risk factor for atherosclerotic vascular disease and are associated with premature myocardial infarction. The role of the endogenous plasminogen activation system in limiting thrombus formation following atherosclerotic plaque disruption is unknown. This study found that genetic deficiency for PAI-1, the primary physiologic regulator of tissue-type plasminogen activator (tPA), prolonged the time to occlusive thrombosis following photochemical injury to carotid atherosclerotic plaque in apolipoprotein E-deficient (apoE−/−) mice. However, anatomic analysis revealed a striking difference in the extent of atherosclerosis at the carotid artery bifurcation between apoE−/− mice and mice doubly deficient for apoE and PAI-1 (PAI-1−/−/apoE−/−). Consistent with a previous report, PAI-1+/+/apoE−/−and PAI-1−/−/apoE−/− mice developed similar atherosclerosis in the aortic arch. The marked protection from atherosclerosis progression at the carotid bifurcation conferred by PAI-1 deficiency suggests a critical role for PAI-1 in the pathogenesis of atherosclerosis at sites of turbulent flow, potentially through the inhibition of fibrin clearance. Consistent with this hypothesis, intense fibrinogen/fibrin staining was observed in atherosclerotic lesions at the carotid bifurcation compared to the aortic arch. These observations identify significant differences in the pathogenesis of atherosclerosis at varying sites in the vascular tree and suggest a previously unappreciated role for the plasminogen activation system in atherosclerosis progression at sites of turbulent flow.

scholarly journals Association between Five Common Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms and Colorectal Cancer Susceptibility

2020 ◽  
Vol 21 (12) ◽  
pp. 4334 ◽  
Author(s):  
Jisu Oh ◽  
Hui Jeong An ◽  
Jung Oh Kim ◽  
Hak Hoon Jun ◽  
Woo Ram Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Plasminogen Activator ◽  
Gene Polymorphisms ◽  
Cancer Susceptibility ◽  
Plasminogen Activator Inhibitor ◽  
Cell Types ◽  
Plasminogen Activator Inhibitor 1 ◽  
Polymerase Chain ◽  
Activator Inhibitor ◽  
Pai 1

The plasminogen activator inhibitor-1 (PAI-1) is expressed in many cancer cell types and modulates cancer growth, invasion, and angiogenesis. The present study investigated the association between five PAI-1 gene polymorphisms and colorectal cancer (CRC) risk. Five PAI-1 polymorphisms (−844G > A [rs2227631], −675 4G > 5G [rs1799889], +43G > A [rs6092], +9785G > A [rs2227694], and +11053T > G [rs7242]) were genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay in 459 CRC cases and 416 controls. Increased CRC risk was more frequently associated with PAI-1 −675 5G5G polymorphism than with 4G4G (adjusted odds ratio (AOR) = 1.556; 95% confidence interval (CI): 1.012–2.391; p = 0.04). In contrast, for the PAI-1 +11053 polymorphism, we found a lower risk of CRC with the GG genotype (AOR = 0.620; 95% CI: 0.413–0.932; p = 0.02) than with the TT genotype, as well as for recessive carriers (TT + TG vs. GG, AOR = 0.662; 95% CI: 0.469–0.933; p = 0.02). The +43AA genotype was associated with lower overall survival (OS) than the +43GG genotype. Our results suggest that the PAI-1 genotype plays a role in CRC risk. This is the first study to identify an association between five PAI-1 polymorphisms and CRC incidence worldwide.

Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4212-4215 ◽  
Author(s):  
Daniel T. Eitzman ◽  
Randal J. Westrick ◽  
Zuojun Xu ◽  
Julia Tyson ◽  
David Ginsburg
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Carotid Bifurcation ◽  
Plasminogen Activation ◽  
Plasminogen Activator Inhibitor 1 ◽  
Atherosclerosis Progression ◽  
Plasminogen Activation System ◽  
Activation System ◽  
Activator Inhibitor ◽  
Pai 1

Dissolution of the fibrin blood clot is regulated in large part by plasminogen activator inhibitor-1 (PAI-1). Elevated levels of plasma PAI-1 may be an important risk factor for atherosclerotic vascular disease and are associated with premature myocardial infarction. The role of the endogenous plasminogen activation system in limiting thrombus formation following atherosclerotic plaque disruption is unknown. This study found that genetic deficiency for PAI-1, the primary physiologic regulator of tissue-type plasminogen activator (tPA), prolonged the time to occlusive thrombosis following photochemical injury to carotid atherosclerotic plaque in apolipoprotein E-deficient (apoE−/−) mice. However, anatomic analysis revealed a striking difference in the extent of atherosclerosis at the carotid artery bifurcation between apoE−/− mice and mice doubly deficient for apoE and PAI-1 (PAI-1−/−/apoE−/−). Consistent with a previous report, PAI-1+/+/apoE−/−and PAI-1−/−/apoE−/− mice developed similar atherosclerosis in the aortic arch. The marked protection from atherosclerosis progression at the carotid bifurcation conferred by PAI-1 deficiency suggests a critical role for PAI-1 in the pathogenesis of atherosclerosis at sites of turbulent flow, potentially through the inhibition of fibrin clearance. Consistent with this hypothesis, intense fibrinogen/fibrin staining was observed in atherosclerotic lesions at the carotid bifurcation compared to the aortic arch. These observations identify significant differences in the pathogenesis of atherosclerosis at varying sites in the vascular tree and suggest a previously unappreciated role for the plasminogen activation system in atherosclerosis progression at sites of turbulent flow.

Regulation of Fibrinolysis in the Development of Atherothrombosis: Role of Adipose Tissue

1999 ◽  
Vol 82 (08) ◽  
pp. 832-836 ◽  
Author(s):  
M.C. Alessi ◽  
I. Juhan-Vague
Keyword(s):  
Adipose Tissue ◽  
Plasminogen Activator Inhibitor ◽  
Cellular Adhesion ◽  
Coronary Risk Factors ◽  
Plasminogen Activator Inhibitor 1 ◽  
Vascular Events ◽  
Insulin Resistant ◽  
Therapeutic Concepts ◽  
And Migration ◽  
Pai 1

IntroductionAmong the list of coronary risk factors, it has recently been proposed that fibrinolytic system impairment, due to increased plasminogen activator inhibitor-1 (PAI-1) levels in plasma, could predict complications of atherosclerosis. The fibrinolytic system1 is regulated by a balance between activators and inhibitors. PAI-1, which inhibits t-PA and u-PA, is the main inhibitor of plasminogen activation. An increased PAI-1 concentration induces a reduction in plasmin formation and leads to fibrin accumulation.2-5 PAI-1 also induces changes in vessel wall remodeling through the activation of metalloproteinases and growth factors and the degradation of the extracellular matrix.4 In addition to its antiprotease activity, PAI-1 also participates in the cellular adhesion and migration processes. Because it binds to vitronectin in the same part of the molecule as vitronectin receptor or u-PA receptor, it mediates the release of cells from their substrate.6,7 All of these properties indicate that PAI-1 can be involved in tissue remodeling and thrombotic processes and, therefore, participates in the development of atherothrombosis.In plasma, an elevated PAI-1 concentration is presently considered a risk factor for coronary vascular events. It appears that PAI-1 is an inducible target controlled for in insulin resistance and obesity, which are situations that favor the development of atherothrombosis. It has been postulated that PAI-1 could contribute to an increased susceptibility to atherothrombosis in insulin-resistant patients. The production of PAI-1 by adipose tissue has recently been demonstrated. The elucidation of the regulation of PAI-1 synthesis and the identification of factors responsible for increased plasma PAI-1 concentration in the insulin-resistant state might lead to therapeutic concepts for the prevention of atherothrombosis.

Characterization of Epitheloid Cells from Human Omentum: Comparison with Endothelial Cells from Umbilical Veins

1991 ◽  
Vol 66 (03) ◽  
pp. 361-367 ◽  
Author(s):  
Y Latron ◽  
M C Alessi ◽  
F George ◽  
F Anfosso ◽  
P Poncelet ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasminogen Activator ◽  
Hormonal Regulation ◽  
Umbilical Vein ◽  
Plasminogen Activator Inhibitor ◽  
Cell Types ◽  
Mesothelial Cells ◽  
Plasminogen Activator Inhibitor 1 ◽  
Umbilical Vein Endothelial Cells ◽  
Pai 1

SummaryCapillary cells represent 95% of the vascular bed, and cells from large and micro-vessels do not express identical functions. In order to study the hormonal regulation of plasminogen activator inhibitor 1 (PAI-1) secretion by human capillary cells we used epithelial cells from omental tissue (HOTMEC). As their endothelial origin is subject to controversy, we attempted to determine their characteristics by comparing them to human umbilical vein endothelial cells (HUVEC). Morphological and biological criteria were studied. By phase contrast microscopy HOTMEC elicited a cobblestone pattern similar to HUVEC. Weibel-Palade bodies were not found in the cytoplasm with electron microscopy. Fluorescence microscopy studies indicated that HOTMEC took up acetylated-LDL more intensely than HUVEC, and showed no staining for von Willebrand factor. The phenotype of HOTMEC was studied by flow cytometry using monoclonal antibodies (mo Ab) directed against epitopes either specific for endothelial cells or for mesothelial cells. We showed that in our preparations only 10% of cells reacted with mo Ab specific for endothelial cells. About 60% of the HOTMEC were labelled with an antibody directed against mesothelial cells. HOTMEC expressed fibrinolytic factors. Tissue plasminogen activator (t-PA) levels in HOTMEC conditioned medium were 50 fold higher than those of HUVEC, and the PAI-1 secretions were identical in both cell types. Insulin which is known to increase PAI-1 synthesis by hepatocytes did not enhance the PAI-1 level either in HOTMEC or in HUVEC conditioned media. Our results suggested that morphological and functional methods did not allow discrimination between the cell types present in the omentum tissue. They also showed that the population obtained from the omental tissue by collagenase digestion is heterogeneous, with few cells expressing endothelial markers.

scholarly journals PAI-1, the Plasminogen System, and Skeletal Muscle

2020 ◽  
Vol 21 (19) ◽  
pp. 7066 ◽  
Author(s):  
Fasih Ahmad Rahman ◽  
Matthew Paul Krause
Keyword(s):  
Skeletal Muscle ◽  
Cell Fate ◽  
Plasminogen Activator Inhibitor ◽  
Cell Types ◽  
Plasminogen Activator Inhibitor 1 ◽  
Disease States ◽  
Muscle Health ◽  
And Function ◽  
Pai 1

The plasminogen system is a critical proteolytic system responsible for the remodeling of the extracellular matrix (ECM). The master regulator of the plasminogen system, plasminogen activator inhibitor-1 (PAI-1), has been implicated for its role in exacerbating various disease states not only through the accumulation of ECM (i.e., fibrosis) but also its role in altering cell fate/behaviour. Examination of PAI-1 has extended through various tissues and cell-types with recent investigations showing its presence in skeletal muscle. In skeletal muscle, the role of this protein has been implicated throughout the regeneration process, and in skeletal muscle pathologies (muscular dystrophy, diabetes, and aging-driven pathology). Needless to say, the complete function of this protein in skeletal muscle has yet to be fully elucidated. Given the importance of skeletal muscle in maintaining overall health and quality of life, it is critical to understand the alterations—particularly in PAI-1—that occur to negatively impact this organ. Thus, we provide a comprehensive review of the importance of PAI-1 in skeletal muscle health and function. We aim to shed light on the relevance of this protein in skeletal muscle and propose potential therapeutic approaches to aid in the maintenance of skeletal muscle health.

scholarly journals Plasminogen activator inhibitor-1 and haemostasis in obesity

2001 ◽  
Vol 60 (3) ◽  
pp. 341-347 ◽  
Author(s):  
Nicola J. Mutch ◽  
Heather M. Wilson ◽  
Nuala A. Booth
Keyword(s):  
Adipose Tissue ◽  
Plasminogen Activator ◽  
Transforming Growth Factor ◽  
Plasminogen Activator Inhibitor ◽  
Cell Types ◽  
Plasminogen Activator Inhibitor 1 ◽  
Increased Risk ◽  
Human Material ◽  
Activator Inhibitor ◽  
Pai 1

The connection between obesity and disordered haemostasis is well established, but incompletely understood. There is a strong link between inhibition of fibrinolysis and obesity, and elevation of the plasma inhibitor, plasminogen activator inhibitor-1 (PAI-1), is regarded as a central factor. Here we explore the increased risk of atherothrombotic disorders in obese subjects, and the evidence for metabolic and genetic causes. There is a clear relationship between plasma PAI-1 and obesity, and adipose tissue synthesises PAI-1, as has been shown in mouse and rat models, and more recently in human material. This tissue also produces several effector molecules that can up regulate PAI-1. These molecules include transforming growth factor b, tumour necrosis factor a, angiotensin II and interleukin 6, all of which up regulate PAI-1 in various cell types. The issue of whether adipose tissue directly contributes to plasma PAI-1, or whether it primarily contributes indirectly, its products stimulating other cells to produce PAI-1 that feeds into the plasma pool, is not yet resolved. Finally, we briefly examine other proteins of haemostasis that are products of adipose tissue. Further studies are needed to define the regulation of these proteins, in adipose tissue itself and in other cells influenced by its products, in order to extend recent insights into the links between obesity and haemostasis.

Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease

2005 ◽  
Vol 93 (04) ◽  
pp. 631-640 ◽  
Author(s):  
Claudia Dellas ◽  
David Loskutoff
Keyword(s):  
Potential Role ◽  
Historical Analysis ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
The Metabolic Syndrome ◽  
And Migration ◽  
The Many ◽  
Activator Inhibitor ◽  
Pai 1

SummaryAlthough plasminogen activator inhibitor 1 (PAI-1) is one of the primary regulators of the fibrinolytic system, it also has dramatic effects on cell adhesion, detachment and migration. PAI-1 also differs from other serine protease inhibitors (serpins) in that it is a trace protein in plasma, it has a short half-life in vivo, its synthesis is highly regulated, and it binds to the adhesive glycoprotein vitronectin (VN) with high affinity and specificity. These unique and diverse properties of PAI-1 probably account for the many observations in the literature that correlate abnormalities in PAI-1 gene expression with a variety of pathological conditions. In this review, we discuss the discovery, origin, properties and regulation of PAI-1, and then speculate about its potential role in vascular disease, fibrosis, obesity and the metabolic syndrome, and cancer.

scholarly journals Plasminogen activator inhibitor-1 impairs plasminogen activationmediated vascular smooth muscle cell apoptosis

2006 ◽  
Vol 96 (11) ◽  
pp. 665-670 ◽  
Author(s):  
Patrick Rossignol ◽  
Eduardo Anglès-Cano ◽  
Henri Lijnen
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Cell Types ◽  
Plasminogen Activation ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

SummaryThe role of plasminogen activator inhibitor-1 (PAI-1) in vascular smooth muscle cell (VSMC) apoptosis mediated by plasminogen activation was studied with the use of aorticVSMC derived from mice with deficiency of PAI-1 (PAI-1-/-), tissue-type (t-PA-/-) or urokinase-type (u-PA-/-) plasminogen activator or from wildtype (WT) mice with corresponding genetic background. Plasminogen incubated with confluentVSMC was activated ina concentration-dependent and saturable manner for all four cell types, with maximal activation rates that were comparable for WT,u-PA-/and t-PA-/cells,but about two-fold higher for PAI-1-/cells. Plasminogen activation was impaired by addition of the lysine analogue 6-aminohexanoic acid, and by addition of t-PA and u-PA neutralizing antibodies, suggesting that it depends on binding to cell surface COOH-terminal lysine residues, and on plasminogen activator activity. Morphological alterations consistent with apoptosis were observed much earlier in PAI-1-/than in WT VSMC. Without addition of plasminogen, the apoptotic index was similar for all four cell types, whereas after incubation with physiological plasminogen concentrations, it was greater in PAI-1-/VSMC, as compared to WT, t-PA-/or u-PA-/VSMC. Furthermore, the apoptotic rate paralleled the release of plasmin. Thus, plasmin-mediated apoptosis of VSMC occurs via plasminogen activation by either t-PA or u-PA and is impaired by PAI-1.

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