scholarly journals Glucagon-like peptide-1 attenuates tumour necrosis factor-α-mediated induction of plasmogen activator inhibitor-1 expression

2007 ◽  
Vol 196 (1) ◽  
pp. 57-65 ◽  
Author(s):  
Hongbin Liu ◽  
Yunshan Hu ◽  
Richard W Simpson ◽  
Anthony E Dear
Keyword(s):  
Endothelial Cell ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Cell Dysfunction ◽  
Tnf Α ◽  
Glucagon Like Peptide 1 ◽  
Factor Α ◽  
Activator Inhibitor ◽  
Necrosis Factor ◽  
Pai 1

Glucagon-like peptide-1 (GLP-1) has been proposed as a target for treatment of type 2 diabetes. GLP-1 has also been demonstrated to improve endothelial cell dysfunction in diabetic patients. Elevated plasmogen activator inhibitor-1 (PAI-1) levels have been implicated in endothelial cell dysfunction. The effect of GLP-1 on PAI-1 expression in vascular endothelial cells has not been explored. In a spontaneously transformed human umbilical vein endothelial cell (HUVEC) line, C11-spontaneously transformed HUVEC (STH) and primary HUVEC cells, GLP-1 treatment, in the presence of a dipeptidyl peptidase IV inhibitor, attenuated induction of PAI-1 protein and mRNA expression by tumour necrosis factor-α (TNF-α). GLP-1 also inhibited the effect of TNF-α on a reporter gene construct harbouring the proximal PAI-1 promoter. In addition, GLP-1 attenuated TNF-α-mediated induction of Nur77 mRNA and TNF-α-mediated binding of nuclear proteins (NPs) to the PAI-1, Nur77, cis-acting response element nerve growth factor induced clone B response element (NBRE). GLP-1 treatment also inhibited TNF-α-mediated induction of Akt phosphorylation. Taken together, these observations suggest that GLP-1 inhibits TNF-α-mediated PAI-1 induction in vascular endothelial cells, and this effect may involve Akt-mediated signalling events and the modulation of Nur77 expression and NP binding to the PAI-1 NBRE.

The Endotoxin-induced Plasminogen Activator Inhibitor-1 Increase in Rabbits Is Not Tumor Necrosis Factor-α Dependent and Can Occur in the Absence of Interleukin-1β

2002 ◽  
Vol 88 (10) ◽  
pp. 639-643 ◽  
Author(s):  
Ramón Montes ◽  
Pablo Rodríguez-Whilhelmi ◽  
Verónica Hurtado ◽  
Akihiro Matsukawa ◽  
Marta Montes ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tnf Α ◽  
Factor Α ◽  
Activator Inhibitor ◽  
Necrosis Factor ◽  
Pai 1

SummaryThe plasminogen activator inhibitor-1 (PAI-1)-dependent fibrinolytic inhibition occurring in endotoxemia contributes to disseminated intravascular coagulation (DIC). Previous findings suggest that tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are responsible for the increase in the level of PAI-1. These observations usually arose from mild endotoxemia models. We analyzed the effect of FR167653, an inhibitor of the TNF-α/IL-1β production, on the PAI-1 levels in rabbits given endotoxin at a dose sufficient to induce DIC: the steep plasma PAI-1 increase was not attenuated by FR167653, in spite of achieving efficient inhibition of the TNF-α production. No IL-1β was detected during endotoxemia. These results suggest that PAI-1 increase might be independent of TNF-α and IL-1β. If these findings applied to humans, therapeutic intervention directing these cytokines would not be useful for the treatment of fibrinolysis in patients with severe sepsis.

scholarly journals A long-acting glucagon-like peptide-1 analogue attenuates induction of plasminogen activator inhibitor type-1 and vascular adhesion molecules

2009 ◽  
Vol 201 (1) ◽  
pp. 59-66 ◽  
Author(s):  
Hongbin Liu ◽  
Anthony E Dear ◽  
Lotte B Knudsen ◽  
Richard W Simpson
Keyword(s):  
Endothelial Cell ◽  
Adhesion Molecule ◽  
Vascular Endothelial Cells ◽  
Plasminogen Activator Inhibitor ◽  
Diabetic Patients ◽  
Vascular Endothelial ◽  
Long Acting ◽  
Activator Inhibitor Type ◽  
Vascular Adhesion ◽  
Pai 1

Glucagon-like peptide-1 (GLP-1) administration attenuates endothelial cell dysfunction in diabetic patients and inhibits tumour necrosis factor α (TNF)-mediated plasminogen activator inhibitor type-1 (PAI-1) induction in human vascular endothelial cells. The short half-life of GLP-1 mediated via degradation by the enzyme dipeptidyl peptidase 4 mandates the clinical use of long-acting GLP-1 analogues. The effects of a long-acting GLP-1 analogue on PAI-1 and vascular adhesion molecule expression in vascular endothelial cells are unknown. In this report, we demonstrate for the first time that the treatment with liraglutide, a long-acting GLP-1 analogue, inhibited TNF or hyperglycaemia-mediated induction of PAI-1, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 mRNA and protein expression in a human vascular endothelial cell line. In addition, treatment attenuated TNF- or hyperglycaemia-mediated induction of the orphan nuclear receptor Nur77 mRNA expression. Taken together, these observations indicate that liraglutide inhibits TNF- or glucose-mediated induction of PAI-1 and vascular adhesion molecule expression, and this effect may involve the modulation of NUR77. These effects suggest that liraglutide may potentially improve the endothelial cell dysfunction associated with premature atherosclerosis identified in type 2 diabetic patients.

scholarly journals GAS6 Inhibits Granulocyte Adhesion to Endothelial Cells

Blood ◽  
1998 ◽  
Vol 91 (7) ◽  
pp. 2334-2340
Author(s):  
Gian Carlo Avanzi ◽  
Margherita Gallicchio ◽  
Flavia Bottarel ◽  
Loretta Gammaitoni ◽  
Giuliana Cavalloni ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Platelet Activating Factor ◽  
Polymorphonuclear Cells ◽  
Vascular Endothelial ◽  
Tnf Α ◽  
High Concentrations ◽  
Adhesive Interactions ◽  
Factor Α ◽  
Dose Dependent

GAS6 is a ligand for the tyrosine kinase receptors Rse, Axl, and Mer, but its function is poorly understood. Previous studies reported that both GAS6 and Axl are expressed by vascular endothelial cells (EC), which play a key role in leukocyte extravasation into tissues during inflammation through adhesive interactions with these cells. The aim of this work was to evaluate the GAS6 effect on the adhesive function of EC. Treatment of EC with GAS6 significantly inhibited adhesion of polymorphonuclear cells (PMN) induced by phorbol 12-myristate 13-acetate (PMA), platelet-activating factor (PAF), thrombin, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), but not that induced by FMLP and IL-8. GAS6 did not affect adhesion to resting EC. Titration experiments showed that high concentrations of GAS6 were needed to inhibit PMN adhesion and that inhibition was dose-dependent at the concentration range of 0.1 to 1 μg/mL. One possibility was that high concentrations were needed to overwhelm the effect of endogenous GAS6 produced by EC. In line with this possibility, treatment of resting EC with soluble Axl significantly potentiated PMN adhesion. Analysis of localization of GAS6 by confocal microscopy and cytofluorimetric analysis showed that it is concentrated along the plasma membrane in resting EC and treatment with PAF induces depletion and/or redistribution of the molecule. These data suggest that GAS6 functions as a physiologic antiinflammatory agent produced by resting EC and depleted when proinflammatory stimuli turn on the proadhesive machinery of EC.

Modulation of sphingosine 1-phosphate/EDG signaling by tumor necrosis factor-α in vascular endothelial cells

2002 ◽  
Vol 108 (2-3) ◽  
pp. 169-174 ◽  
Author(s):  
Makoto Osada ◽  
Yutaka Yatomi ◽  
Tsukasa Ohmori ◽  
Shigemi Hosogaya ◽  
Yukio Ozaki
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Vascular Endothelial Cells ◽  
Vascular Endothelial ◽  
Sphingosine 1 Phosphate ◽  
Factor Α ◽  
Necrosis Factor

Involvement of NADPH oxidase in oxidized LDL-induced upregulation of heat shock factor-1 and plasminogen activator inhibitor-1 in vascular endothelial cells

2009 ◽  
Vol 297 (1) ◽  
pp. E104-E111 ◽  
Author(s):  
Ruozhi Zhao ◽  
Xiuli Ma ◽  
Xueping Xie ◽  
Garry X. Shen
Keyword(s):  
Endothelial Cells ◽  
Vascular Endothelial Cells ◽  
Oxidized Ldl ◽  
Plasminogen Activator Inhibitor ◽  
Heat Shock Factor 1 ◽  
Vascular Endothelial ◽  
Plasminogen Activator Inhibitor 1 ◽  
Induced Expression ◽  
Activator Inhibitor ◽  
Pai 1

Plasminogen activator inhibitor-1 (PAI-1) is implicated in thrombogenesis, inflammation, and extracellular matrix remodeling. Previous studies indicated that oxidized low-density lipoprotein (LDL) stimulated the generation of PAI-1 in vascular endothelial cells (EC). The present study demonstrated that LDL oxidized by copper, iron, or 3-morpholinosydnonimine increased the expression of NADPH oxidase (NOX) 2, PAI-1, and heat shock factor-1 (HSF1) in human umbilical vein EC or coronary artery EC compared with LDL or vehicle. Diphenyleneiodonium, a NOX inhibitor, prevented the increases of the expression of HSF1 and PAI-1 in EC induced by oxidized LDLs. Small-interference RNA (siRNA) for p22phox, an essential subunit of NOX, prevented oxidized LDL-induced expression of NOX2, HSF1, and PAI-1 in EC. HSF1 siRNA inhibited oxidized LDL-induced expression of PAI-1 and HSF1, but not NOX2, in EC. The binding of HSF1 to PAI-1 promoter and the activity of PAI-1 promoter in EC were enhanced by oxidized LDL. Butylated hydroxytulene, a potent antioxidant, inhibited oxidized LDL-induced release of hydrogen peroxide (H2O2) and the expression of NOX2, HSF1, and PAI-1 in EC. Treatment with H2O2 increased the abundance of NOX2, HSF1, and PAI-1 in EC. The results of the present study indicate that oxidized LDL-induced expression of NOX may lead to the elevated release of reactive oxygen species, the activation of HSF1, and the enhancement of the transcription of PAI-1 gene in cultured vascular EC.

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