Adipocytes derived fibrinolytic components in peritoneum — a pilot study

Open Medicine ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. 604-609
Author(s):  
Sylvie Opatrna ◽  
Marie Korabečná ◽  
Věra Křížková ◽  
Zbynek Tonar ◽  
Jitka Kočová ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Plasminogen Activator ◽  
Cellular Localization ◽  
Plasminogen Activator Inhibitor ◽  
Immunohistochemical Localization ◽  
Related Factors ◽  
Mutual Correlation ◽  
Transport Characteristic ◽  
Diabetes Status ◽  
Pai 1

AbstractThe proteins of the fibrinolytic system — urokinase plasminogen activator(uPA), tissue plasminogen activator (tPA)and plasminogen activator inhibitor type IPAI-I) — play important roles in fibrotization in various organs and including peritoneum. To study the cellular localization of PAI-1, tPA and uPA within the adipose tissue of the peritoneal membrane in patients at the onset of peritoneal dialysis(PD) we determined the initial expression of these proteins in relationship to multiple clinical variables. Methods: routinely performed parietal peritoneal biopsies in 12 patients undergoing peritoneal catheter implantation were examined. We used formalinfixed, paraffin-embedded specimens for immunohistochemical localization of these proteins along with the stereological pointcounting method for quantification of their expression within the peritoneal adipose tissue. Results: strong positive mutual correlation between the expression of PAI-1 and both uPA (SpearmanR=0.66) and tPA (R=0.59) as well as between the expression of uPA and tPA (R=0.77) was found without any relatioship to BMI, age, peritoneal transport characteristic or diabetes status. Conclusion: Adipose tissue within the peritoneum is capable of producing fibrinolysis regulators (independently on clinical parameters) thus possibly affecting the fibrotization and function of peritoneum as dialysis membrane. The effect of dialysis solution dosing, composition and other dialysis related factors should be clarified in future studies.

Impairment of adipose tissue development by hypoxia is not mediated by plasminogen activator inhibitor-1

2006 ◽  
Vol 95 (01) ◽  
pp. 174-181 ◽  
Author(s):  
Fabrizio Semeraro ◽  
Gabor Voros ◽  
Désiré Collen ◽  
H. Lijnen
Keyword(s):  
Adipose Tissue ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Development ◽  
Plasminogen Activator Inhibitor 1 ◽  
Adipose Tissue Development ◽  
Activator Inhibitor ◽  
Pai 1

SummaryHypoxia in rodents and humans is associated with a reduction of body fat on the one hand, and with enhanced expression of plasminogen activator inhibitor-1 (PAI-1), the main inhibitor of the fibrinolytic system, on the other hand. It was the objective of this study to investigate whether impairment of adipose tissue development by hypoxia may be mediated by PAI-1. Five week old male wild-type (WT) C57Bl/6 mice were fed a standard (SFD) or high fat (HFD) diet and kept under normoxic or hypoxic (10% O2) conditions. In addition, PAI-1 deficient mice and WT littermates were kept on HFD under normoxia or hypoxia. In vitro, the effect of hypoxia (2% O2) was investigated on differentiation of 3T3-L1 cells into adipocytes. Hypoxia induced a significant reduction of weight gain in WT mice on either SFD or HFD, accompanied by lower weights of subcutaneous (SC) and gonadal (GON) fat. Under hypoxic conditions, adipocytes in the adipose tissues were significantly smaller, whereas blood vessel size and density were larger. Serum PAI-1 levels were enhanced in hypoxic mice on SFD but not on HFD, and overall did not correlate with the observed changes in adipose tissue composition. Furthermore, the effects of hypoxia on adipose tissue in mice on HFD were not affected by deficiency of PAI-1. The inhibiting effect of hypoxia on in vitro preadipocyte differentiation was not mediated by PAI-1 activity. In conclusion, impairment of in vivo adipose tissue development and in vitro differentiation of preadipocytes by hypoxia is not mediated by PAI-1.

scholarly journals The Role of Plasminogen Activator Inhibitor-1 in the Metabolic Syndrome and Its Regulation

2014 ◽  
Vol 3 (6) ◽  
pp. 36 ◽  
Author(s):  
Martha Phelan ◽  
David M. Kerins
Keyword(s):  
Risk Factors ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
The Metabolic Syndrome ◽  
Activator Inhibitor ◽  
Pai 1

<p>Obesity is a major risk factor for cardiovascular disease (CVD). Lipid abnormalities, hypertension, impaired glucose tolerance or diabetes, are cardiovascular risk factors that are frequently present in patients with obesity. Haemostatic and fibrinolytic disturbances are also considered to be important risk factors for CVD hence, a potential link between CVD, obesity and the metabolic syndrome arises. Regulation of the fibrinolytic system can occur at the level of plasminogen activators and plasminogen activator inhibitor-1 (PAI-1). PAI-1, a glycoprotein, is one of the most important inhibitors of fibrinolysis. Regulation of this serine protease inhibitor may have a beneficial effect on other conditions associated with the metabolic syndrome. Human adipose tissue is a source of PAI-1. PAI-1 production may in turn be controlled by a number of hormones and cytokines which are secreted by adipose tissue in addition to dietary factors. In this review we summarise the current knowledge regarding the role of altered fibrinolytic function in obesity, CVD and hence the metabolic syndrome. Regulatory factors including different dietary components, weight loss and dietary intervention will also be discussed.</p>

Effect of plasminogen activator inhibitor-1 deficiency on nutritionally-induced obesity in mice

2005 ◽  
Vol 93 (05) ◽  
pp. 816-819 ◽  
Author(s):  
Roger Lijnen
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Plasminogen Activator ◽  
High Fat Diet ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
High Fat ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

SummaryPlasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of tissue-type (t-PA) and urokinase-type (u-PA) plasminogen activator. Recent studies in murine models have yielded apparently conflicting data on a potential role of PAI-1 in adipose tissue development and obesity. To reinvestigate this issue, we have rederived PAI-1 deficient (PAI-1-/-) and wild-type (WT) mice and generated true littermates in a 81.25% C57Bl/6: 18.75% 129 SV genetic background. Male 5-week-old PAI-1-/- and WT mice were kept on a high fat diet (20.1 kJ/g) for 15 weeks. Body weight gain was comparable for both genotypes, and at the time of sacrifice total body weights (39 ± 1.1 versus 41 ± 1.2 g) as well as the weights of subcutaneous (SC, 1,520 ± 110 versus 1,480 ± 110 mg) adipose tissue were not significantly different. In contrast, the gonadal (GON, 1,900 ± 43 versus 1,510 ± 86 mg, p < 0.005) tissue mass was larger in PAI-1-/- mice. Plasma levels of insulin, leptin, glucose, triglycerides, total, HDL and LDL cholesterol were comparable for both genotypes. Immunohisto-chemical analysis of SC and GON adipose tissues did not reveal differences in adipocyte size or number between both genotypes, whereas blood vessel density was also comparable for GON fat but lower in SC fat of WT mice. Thus, this study in littermate mice on high fat diet did not reveal an effect of PAI-1 deficiency on body weight, and a differential effect on SC and GON adipose tissue.

Stimulated in vivo synthesis of plasminogen activator inhibitor-1 in human adipose tissue

2012 ◽  
Vol 108 (09) ◽  
pp. 485-492 ◽  
Author(s):  
Jan Liska ◽  
Per Eriksson ◽  
Eva Sverremark-Ekström ◽  
Per Tornvall ◽  
Mattias Ekström
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Adipose Tissue ◽  
Plasminogen Activator ◽  
Systemic Inflammation ◽  
Plasminogen Activator Inhibitor ◽  
Human Adipose Tissue ◽  
Omental Adipose Tissue ◽  
Pai 1

SummaryPlasminogen activator inhibitor type-1 (PAI-1) is one of the most important inhibitors of endogenous fibrinolysis. Adipose tissue is a suggested source of the elevated plasma levels of PAI-1 in obesity. The relation between PAI-1 and inflammation is of particular interest, but current knowledge regarding regulation of PAI-1 in adipose tissue is mainly based on animal studies or ex vivo experiments on human cultured adipocytes. So far, no study has described stimulated gene expression and protein synthesis of PAI-1 in vivo in human adipose tissue. We used open heart surgery as a model of acute systemic inflammation. Twenty-two male patients underwent blood sampling and omental and subcutaneous adipose tissue biopsies for gene expression studies before and after surgery. Expression and localisation of PAI-1 antigen was evaluated by immunohistochemistry. After surgery gene expression of PAI-1 increased 27-fold in omental adipose tissue and three-fold in subcutaneous adipose tissue, but no differences were found in tissue-type plasminogen activator (t-PA) mRNA. PAI-1 antigen was localised within endothelial cells and in the adipose tissue interstitium close to vessels. The upregulated gene expression and protein synthesis in adipose tissue was followed by increased concentrations of PAI-1 antigen in plasma. In conclusion, we present for the first time that an acute systemic inflammation in humans increased gene expression and protein synthesis of PAI-1 in adipose tissue and that this increase was most prominent in omental adipose tissue. PAI-1 synthesis in adipose tissue due to acute systemic inflammation may be a link between inflammation and impaired endogenous fibrinolysis.

Inhibition by fibrates of plasminogen activator inhibitor type-1 expression in human adipocytes and preadipocytes

2009 ◽  
Vol 101 (06) ◽  
pp. 1060-1069 ◽  
Author(s):  
Sandra Ernst ◽  
Anne Leugers ◽  
Florian Willecke ◽  
Burton Sobel ◽  
Christoph Bode ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor Type ◽  
Inhibitor Type ◽  
Activator Inhibitor Type ◽  
Adipose Cells ◽  
Activator Inhibitor ◽  
Pai 1

SummaryPlasminogen activator inhibitor type-1 (PAI-1), an established marker and mediator of cardiovascular risk, is produced extensively in adipose tissue. Fibrates are hypolipidemic peroxisome proliferator activated receptor-alpha (PPARα) agonists. Recent laboratory and clinical observations indicate that they are also anti-atherosclerotic. Mechanisms responsible, however, remain to be fully understood. The present study was designed to elucidate modulation of PAI-1 expression in adipose cells by fibrates as a potential mechanism. Expression of PPARα was verified by PCR, immunohistochemistry, and Western blotting. In cultured preadipocytes and adipocytes gemfibrozil and fenofibrate significantly reduced PAI-1 protein expression by up to 55 ± 5% and 34 ± 4% under basal conditions and up to 56 ± 6% and 31 ± 6% under conditions of stimulation of the cells with 40 pM trans-Keywords forming growth factor (TGF)β, respectively. Quantification of mRNA showed that the gemfibrozil-induced effect was at least in part regulated at the transcriptional level. Incubations with non-fibrate PPARα agonists showed similar reductions in PAI-1 expression. The decrease in PAI-1 expression induced by gemfibrozil was inhibited by MK886, a PPARα inhibitor. Furthermore, preadipocytes isolated from PPARα-deficient mice produced significantly more PAI-1 than those from wild-type mice upon stimulation with TGFβ. Finally, fenofibrate reduced PAI-1 expression both in plasma and adipose tissue of hyperlipidemic mice. Our data support the view that PPARα activation down-regulates PAI-expression in adipose cells that may contribute in part to the reduction in cardiovascular mortality seen with fibrates in clinical trials.

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.

scholarly journals Plasminogen Activator Inhibitor-1 is Regulated Through Dietary Fat Intake and Heritability: Studies in Twins

2017 ◽  
Vol 20 (4) ◽  
pp. 338-348 ◽  
Author(s):  
Anna Janina Engstler ◽  
Turid Frahnow ◽  
Michael Kruse ◽  
Andreas Friedrich Hermann Pfeiffer ◽  
Ina Bergheim
Keyword(s):  
Adipose Tissue ◽  
Mrna Expression ◽  
Plasminogen Activator ◽  
Plasma Concentrations ◽  
Plasminogen Activator Inhibitor ◽  
Fatty Tissue ◽  
Plasminogen Activator Inhibitor 1 ◽  
The Impact ◽  
Activator Inhibitor ◽  
Pai 1

In different pathophysiological conditions plasminogen activator inhibitor-1 (PAI-1) plasma concentrations are elevated. As dietary patterns are considered to influence PAI-1 concentration, we aimed to determine active PAI-1 plasma concentrations and mRNA expression in adipose tissue before and after consumption of a high-fat diet (HFD) and the impact of additive genetic effects herein in humans. For 6 weeks, 46 healthy, non-obese pairs of twins (aged 18–70) received a normal nutritionally balanced diet (ND) followed by an isocaloric HFD for 6 weeks. Active PAI-1 plasma levels and PAI-1 mRNA expression in subcutaneous adipose tissue were assessed after the ND and after 1 and 6 weeks of HFD. Active PAI-1 plasma concentrations and PAI-1 mRNA expression in adipose tissue were significantly increased after both 1 and 6 weeks of HFD when compared to concentrations determined after ND (p< .05), with increases of active PAI-1 being independent of gender, age, or changes of BMI and intrahepatic fat content, respectively. However, analysis of covariance suggests that serum insulin concentration significantly affected the increase of active PAI-1 plasma concentrations. Furthermore, the increase of active PAI-1 plasma concentrations after 6 weeks of HFD was highly heritable (47%). In contrast, changes in PAI-1 mRNA expression in fatty tissue in response to HFD showed no heritability and were independent of all tested covariates. In summary, our data suggest that even an isocaloric exchange of macronutrients — for example, a switch to a fat-rich diet — affects PAI-1 concentrations in humans and that this is highly heritable.

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