scholarly journals Gastric Expression of Plasminogen Activator Inhibitor (PAI)-1 Is Associated with Hyperphagia and Obesity in Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (2) ◽  
pp. 718-726 ◽  
Author(s):  
Susan Kenny ◽  
Joanne Gamble ◽  
Suzanne Lyons ◽  
Nikolina Vlatković ◽  
Rod Dimaline ◽  
...  
Keyword(s):  
Food Intake ◽  
Plasminogen Activator ◽  
Nucleus Tractus Solitarius ◽  
Plasma Concentrations ◽  
Plasminogen Activator Inhibitor ◽  
Wild Type ◽  
Urokinase Plasminogen Activator Receptor ◽  
Obesity In Mice ◽  
Activator Inhibitor ◽  
Pai 1

The adipokine plasminogen activator inhibitor (PAI)-1 is increased in plasma of obese individuals and exhibits increased expression in the stomachs of individuals infected with Helicobacter. To investigate the relevance of gastric PAI-1, we used 1.1 kb of the H+/K+β subunit promoter to overexpress PAI-1 specifically in mouse gastric parietal cells (PAI-1-H/Kβ mice). We studied the physiological, biochemical, and behavioral characteristics of these and mice null for PAI-1 or a putative receptor, urokinase plasminogen activator receptor (uPAR). PAI-1-H/Kβ mice had increased plasma concentrations of PAI-1 and increased body mass, adiposity, and hyperphagia compared with wild-type mice. In the latter, food intake was inhibited by cholecystokinin (CCK)8s, but PAI-1-H/Kβ mice were insensitive to the satiating effects of CCK8s. PAI-1-H/Kβ mice also had significantly reduced expression of c-fos in the nucleus tractus solitarius in response to CCK8s and refeeding compared with wild-type mice. Exogenous PAI-1 reversed the effects of CCK8s on food intake and c-fos levels in the nucleus tractus solitarius of wild-type mice, but not uPAR-null mice. Infection of C57BL/6 mice with Helicobacter felis increased gastric abundance of PAI-1 and reduced the satiating effects of CCK8s, whereas the response to CCK8s was maintained in infected PAI-1–null mice. In cultured vagal afferent neurons, PAI-1 inhibited stimulation of neuropeptide Y type 2 receptor (Y2R) expression by CCK8s. Thus, gastric expression of PAI-1 is associated with hyperphagia, moderate obesity, and resistance to the satiating effects of CCK indicating a new role in suppressing signals from the upper gut that inhibit food intake.

The plasminogen activator inhibitor-1 (PAI-1) promoter haplotype is related to PAI-1 plasma concentrations in lean individuals

2005 ◽  
Vol 181 (2) ◽  
pp. 275-284 ◽  
Author(s):  
Maartje Verschuur ◽  
Annemarie Jellema ◽  
Else M. Bladbjerg ◽  
Edith J. M. Feskens ◽  
Ronald P. Mensink ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Plasma Concentrations ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1 ◽  
Promoter Haplotype

Fibrate-modulated Expression of Fibrinogen, Plasminogen Activator Inhibitor-1 and Apolipoprotein A-I in Cultured Cynomolgus Monkey Hepatocytes

1998 ◽  
Vol 80 (12) ◽  
pp. 942-948 ◽  
Author(s):  
M. Kockx ◽  
H. M. G. Princen ◽  
T. Kooistra
Keyword(s):  
Plasminogen Activator ◽  
Cynomolgus Monkey ◽  
Plasma Concentrations ◽  
Plasminogen Activator Inhibitor ◽  
Peroxisome Proliferator ◽  
Plasminogen Activator Inhibitor 1 ◽  
Apolipoprotein A ◽  
Activator Inhibitor ◽  
Pai 1

SummaryFibrates are used to lower plasma triglycerides and cholesterol levels in hyperlipidemic patients. In addition, fibrates have been found to alter the plasma concentrations of fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and apolipoprotein A-I (apo A-I). We have investigated the in vitro effects of fibrates on fibrinogen, PAI-1 and apo A-I synthesis and the underlying regulatory mechanisms in primary monkey hepatocytes.We show that fibrates time- and dose-dependently increase fibrinogen and apo A-I expression and decrease PAI-1 expression in cultured cynomolgus monkey hepatocytes, the effects demonstrating different potency for different fibrates. After three consecutive periods of 24 h the most effective fibrate, ciprofibrate (at 1 mmol/l), increased fibrinogen and apo A-I synthesis to 356% and 322% of control levels, respectively. Maximum inhibition of PAI-1 synthesis was about 50% of control levels and was reached by 1 mmol/l gemfibrozil or ciprofibrate after 48 h. A ligand for the retinoid-X-receptor (RXR), 9-cis retinoic acid, and specific activators of the peroxisome proliferator-activated receptor-α (PPARα), Wy14,643 and ETYA, influenced fibrinogen, PAI-1 and apo A-I expression in a similar fashion, suggesting a role for the PPARα/RXRα heterodimer in the regulation of these genes. When comparing the effects of the various compounds on PPARα trans-activation activity as determined in a PPARα-sensitive reporter gene system and the ability of the compounds to affect fibrinogen, PAI-1 and apo A-I antigen production, a good correlation (r = 0.80; p <0.01) between PPARα transactivation and fibrinogen expression was found. Apo A-I expression correlated only weakly with PPARα transactivation activity (r = 0.47; p = 0.24), whereas such a correlation was absent for PAI-1 (r = 0.03; p = 0.95). These results strongly suggest an involvement of PPARα in the regulation of fibrinogen gene expression.

Vascular release of plasminogen activator inhibitor-1 impairs fibrinolysis during acute arterial thrombosis in mice

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 153-160
Author(s):  
Tomihisa Kawasaki ◽  
Mieke Dewerchin ◽  
Henri R. Lijnen ◽  
Jos Vermylen ◽  
Marc F. Hoylaerts
Keyword(s):  
Carotid Artery ◽  
Plasminogen Activator ◽  
Thrombus Formation ◽  
Blood Platelets ◽  
Plasma Concentrations ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Deficient Mice ◽  
Activator Inhibitor ◽  
Pai 1

The role of plasminogen activator inhibitor-1 (PAI-1) in the plasma, blood platelets, and vessel wall during acute arterial thrombus formation was investigated in gene-deficient mice. Photochemically induced thrombosis in the carotid artery was analyzed via transillumination. In comparison to thrombosis in C57BL/6J wild-type (wt) mice (113 ± 19 × 106 arbitrary light units [AU] n = 15, mean ± SEM), thrombosis in PAI-1−/− mice (40 ± 10 × 106 AU, n = 13) was inhibited (P < .01), indicating that PAI-1 controls fibrinolysis during thrombus formation. Systemic administration of murine PAI-1 into PAI-1−/− mice led to a full recovery of thrombotic response. Occurrence of fibrinolytic activity was confirmed in 2-antiplasmin (2-AP)–deficient mice. The sizes of thrombi developing in wt mice, in 2-AP+/− and 2-AP−/− mice were 102 ± 35, 65 ± 8.1, and 13 ± 6.1 × 106 AU, respectively (n = 6 each) (P < .05), compatible with functional plasmin inhibition by 2-AP. In contrast, thrombi in wt mice, t-PA−/− and u-PA−/−mice were comparable, substantiating efficient inhibition of fibrinolysis by the combined PAI-1/2-AP action. Platelet depletion and reconstitution confirmed a normal thrombotic response in wt mice, reconstituted with PAI-1−/− platelets, but weak thrombosis in PAI-1−/− mice reconstituted with wt platelets. Accordingly, murine (wt) PAI-1 levels in platelet lysates and releasates were 0.43 ± 0.09 ng/109 platelets and plasma concentrations equaled 0.73 ± 0.13 ng/mL. After photochemical injury, plasma PAI-1 rose to 2.9 ± 0.7 ng/mL (n = 9, P < .01). The plasma rise was prevented by ligating the carotid artery. Hence, during acute thrombosis, fibrinolysis is efficiently prevented by plasma 2-AP, but also by vascular PAI-1, locally released into the circulation after endothelial injury.

Effect of Stabilizing versus Destabilizing Interactions on Plasminogen Activator Inhibitor-1

2000 ◽  
Vol 84 (11) ◽  
pp. 871-875 ◽  
Author(s):  
Nele Vleugels ◽  
John Leys ◽  
Isabelle Knockaert ◽  
Paul Declerck
Keyword(s):  
Plasminogen Activator ◽  
Half Life ◽  
Plasminogen Activator Inhibitor ◽  
Reactive Site ◽  
Wild Type ◽  
Plasminogen Activator Inhibitor 1 ◽  
The Stability ◽  
Gate Region ◽  
Activator Inhibitor ◽  
Pai 1

SummaryPlasminogen activator inhibitor-1 (PAI-1) is a unique member of the serpin family, as it spontaneously converts into a latent conformation. However, the exact mechanism of this conversion is not known. Previous studies reported that neutralizing monoclonal antibodies as well as reversal or removal of charges on the s3C-s4C turn results in a destabilization of PAI-1 leading to an accelerated conversion to its latent form.In this study the effect of the reversal or removal of charges in this “gate region” (R186E/R187E, H190E/K191E, H190L/K191L and R356E) on a stable PAI-1-variant (PAI-1-stab) was investigated. Whereas PAI-1-stab has a half-life of 150 ± 66 h, PAI-1-stab-R186ER187E, PAI-1-stab-H190E-K191E, PAI-1-stab-H190L-K191L and PAI-1-stab-R356E have a strongly decreased half-life (p< 0.005 versus PAI-1-stab) of 175 ± 48 min, 75 ± 34 min, 68 ± 38 min and 79 ± 16 min, respectively. Wild-type PAI-1 (wtPAI-1) had a half-life of 55 ± 19 min. These data indicate that the stabilization induced by the mutated residues in PAI-1-stab is counteracted by the additional mutations, resulting in half-lives similar to that of wtPAI-1, thereby suggesting that the stabilizing and destabilizing forces act mainly independently in these mutants. Extrapolation of these data to other (stable) serpins leads to the hypothesis that the s3C-s4C turn and the distal hinge region of the reactive site loop plays a role for the stability of serpins in general.

scholarly journals Plasminogen Activator Inhibitor-Type I Gene Deficient Mice Show Reduced Influx of Neutrophils in Ventilator-Induced Lung Injury

2011 ◽  
Vol 2011 ◽  
pp. 1-11
Author(s):  
Esther K. Wolthuis ◽  
Alexander P. J. Vlaar ◽  
Jorrit-Jan H. Hofstra ◽  
Joris J. T. H. Roelofs ◽  
Vivian de Waard ◽  
...  
Keyword(s):  
Lung Injury ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Lavage Fluid ◽  
Type I ◽  
Wild Type ◽  
Ventilator Induced Lung Injury ◽  
Deficient Mice ◽  
Activator Inhibitor ◽  
Pai 1

Ventilator-induced lung injury (VILI) is associated with inhibition of the fibrinolytic system secondary to increased production of plasminogen activator inhibitor- (PAI-)1. To determine the role of PAI-1 on pulmonary coagulopathy and inflammation during mechanical ventilation, PAI-1 gene-deficient mice and their wild-type littermates were anesthetized (control), or anesthetized, tracheotomized and subsequently ventilated for 5 hours with either low tidal volumes () or high tidal volumes (). VILI was assessed by pulmonary coagulopathy, lung wet-to-dry ratios, total protein level in bronchoalveolar lavage fluid, neutrophil influx, histopathology, and pulmonary and plasma cytokine levels. Ventilation resulted in pulmonary coagulopathy and inflammation, with more injury following ventilation with as compared to . In PAI-1 gene-deficient mice, the influx of neutrophils in the pulmonary compartment was attenuated, while increased levels of pulmonary cytokines were found. Other endpoints of VILI were not different between PAI-1 gene-deficient and wild-type mice. These data indicate that a defect fibrinolytic response attenuates recruitment of neutrophils in VILI.

scholarly journals Functional Stability of Plasminogen Activator Inhibitor-1

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Songul Yasar Yildiz ◽  
Pinar Kuru ◽  
Ebru Toksoy Oner ◽  
Mehmet Agirbasli
Keyword(s):  
Plasminogen Activator ◽  
Biological Effects ◽  
Critical Role ◽  
Plasma Concentrations ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Plasminogen Activator Inhibitor 1 ◽  
Type Plasminogen Activator ◽  
Activator Inhibitor ◽  
Pai 1

Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of plasminogen activators, such as tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), and a major regulator of the fibrinolytic system. PAI-1 plays a pivotal role in acute thrombotic events such as deep vein thrombosis (DVT) and myocardial infarction (MI). The biological effects of PAI-1 extend far beyond thrombosis including its critical role in fibrotic disorders, atherosclerosis, renal and pulmonary fibrosis, type-2 diabetes, and cancer. The conversion of PAI-1 from the active to the latent conformation appears to be unique among serpins in that it occurs spontaneously at a relatively rapid rate. Latency transition is believed to represent a regulatory mechanism, reducing the risk of thrombosis from a prolonged antifibrinolytic action of PAI-1. Thus, relying solely on plasma concentrations of PAI-1 without assessing its function may be misleading in interpreting the role of PAI-1 in many complex diseases. Environmental conditions, interaction with other proteins, mutations, and glycosylation are the main factors that have a significant impact on the stability of the PAI-1 structure. This review provides an overview on the current knowledge on PAI-1 especially importance of PAI-1 level and stability and highlights the potential use of PAI-1 inhibitors for treating cardiovascular disease.

The upstream stimulatory factor-2a inhibits plasminogen activator inhibitor-1 gene expression by binding to a promoter element adjacent to the hypoxia-inducible factor-1 binding site

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2657-2666 ◽  
Author(s):  
Anatoly Samoylenko ◽  
Ulrike Roth ◽  
Kurt Jungermann ◽  
Thomas Kietzmann
Keyword(s):  
Plasminogen Activator ◽  
Hypoxia Inducible Factor ◽  
Plasminogen Activator Inhibitor ◽  
Wild Type ◽  
Upstream Stimulatory Factor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Hypoxia Inducible Factor 1 ◽  
Stimulatory Factor ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Plasminogen activator inhibitor-1 (PAI-1) expression is induced by hypoxia (8% O2) via the PAI-1 promoter region −175/−159 containing a hypoxia response element (HRE-2) binding the hypoxia-inducible factor-1 (HIF-1) and an adjacent response element (HRE-1) binding a so far unknown factor. The aim of the present study was to identify this factor and to investigate its role in the regulation of PAI-1 expression. It was found by supershift assays that the upstream stimulatory factor-2a (USF-2a) bound mainly to the HRE-1 of the PAI-1 promoter and to a lesser extent to HRE-2. Overexpression of USF-2a inhibited PAI-1 messenger RNA and protein expression and activated L-type pyruvate kinase expression in primary rat hepatocytes under normoxia and hypoxia. Luciferase (Luc) gene constructs driven by 766 and 276 base pairs of the 5′-flanking region of the PAI-1 gene were transfected into primary hepatocytes together with expression vectors encoding wild-type USF-2a and a USF-2a mutant lacking DNA binding and dimerization activity (ΔHU2a). Cotransfection of the wild-type USF-2a vector reduced Luc activity by about 8-fold, whereas cotransfection of ΔHU2a did not influence Luc activity. Mutation of the HRE-1 (−175/−168) in the PAI-1 promoter Luc constructs decreased USF-dependent inhibition of Luc activity. Mutation of the HRE-2 (−165/−158) was less effective. Cotransfection of a HIF-1α vector could compete for the binding of USF at HRE-2. These results indicated that the balance between 2 transcriptional factors, HIF-1 and USF-2a, which can bind adjacent HRE sites, appears to be involved in the regulation of PAI-1 expression in many clinical conditions.

Types 1 and 2 Plasminogen Activator lnhibitor and Tirmor Necrosis Factor Alpha in Fatients with Sepsis

1990 ◽  
Vol 64 (01) ◽  
pp. 003-006 ◽  
Author(s):  
J A Páramo ◽  
J L Pérez ◽  
M Serrano ◽  
E Rochal
Keyword(s):  
Plasminogen Activator ◽  
Plasma Concentrations ◽  
Plasminogen Activator Inhibitor ◽  
Necrosis Factor Alpha ◽  
Human Sepsis ◽  
Tnf Α ◽  
Gram Negative Bacteremia ◽  
Activator Inhibitor ◽  
Necrosis Factor ◽  
Pai 1

SummaryWe have determined the plasma concentrations of types 1 and 2 of plasminogen activator inhibitor (PAI-1 and PAI-2), tumor necrosis factor (TNF-α) and endotoxin in 47 patients with bacterial infection (22 patients presented with positive blood cultures). Results were compared with those observed in 30 healthy subjects. There was a significant increase in PAI-1 and TNF-α in patients as compared to controls (p <0.0001), whereas no differences for PAI-2 were observed. PAI-1 and TNF-α were significantly higher in 18 patients with gram-negative bacteremia as compared to all other patients (p <0.0001). However, no correlation between the analyzed parameters and either endotoxin or clinical outcome was observed. We conclude that there is an increase of PAI-1 and TNF-α in patients with sepsis, which is not related to the endotoxin concentration. Our results suggest that PAI-1, but not PAI-2, is the main plasminogen activator inhibitor in human sepsis.

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