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 Human vascular adhesion protein 1 (VAP-1) is a unique sialoglycoprotein that mediates carbohydrate-dependent binding of lymphocytes to endothelial cells.

1996 ◽  
Vol 183 (2) ◽  
pp. 569-579 ◽  
Author(s):  
M Salmi ◽  
S Jalkanen
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Vascular Endothelial Cells ◽  
Lymphoid Tissues ◽  
Vascular Endothelial ◽  
Adhesion Protein ◽  
Culture Model ◽  
Vascular Adhesion ◽  
Vascular Adhesion Protein 1

The regulated interactions of leukocytes with vascular endothelial cells are crucial in controlling leukocyte traffic between blood and tissues. Vascular adhesion protein-1 (VAP-1) is a novel, human endothelial cell molecule that mediates tissue-selective lymphocyte binding. Two species (90 and 170 kD) of VAP-1 exist in lymphoid tissues. Glycosidase digestions revealed that the mature 170-kD form of VAP-1 expressed on the lumenal surfaces of vessels is a heavily sialylated glycoprotein. The sialic acids are indispensable for the function of VAP-1, since the desialylated form of VAP-1 no longer mediates lymphocyte binding. We also show that L-selectin is not required for binding of activated lymphocytes to VAP-1 under conditions of shear stress. The 90-kD form of VAP-1 was only seen in an organ culture model, and may represent a monomeric or proteolytic form of the larger species. These data indicate that L-selectin negative lymphocytes can bind to tonsillar venules via the VAP- 1-mediated pathway. Moreover, our findings extend the role of carbohydrate-mediated binding in lymphocyte-endothelial cell interactions beyond the known selectins. In conclusion, VAP-1 naturally exists as a 170-kD sialoglycoprotein that uses sialic acid residues to interact with its counter-receptors on lymphocytes under nonstatic conditions.

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.

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.

Apposition-Dependent Induction of Plasminogen Activator Inhibitor Type 1 Expression: A Mechanism for Balancing Pericellular Proteolysis During Angiogenesis

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 939-945 ◽  
Author(s):  
Eran Bacharach ◽  
Ahuva Itin ◽  
Eli Keshet
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
L Cells ◽  
Inhibitor Type ◽  
Activator Inhibitor Type ◽  
Pericellular Proteolysis ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Plasminogen-activator inhibitor type I (PAI-1), the primary inhibitor of urinary-type plasminogen activator, is thought to play an important role in the control of stroma invasion by both endothelial and tumor cells. Using an in vitro angiogenesis model of capillary extension through a preformed monolayer, in conjunction with in situ hybridization analysis, we showed that PAI-1 mRNA is specifically induced in cells juxtaposed next to elongating sprouts. To further establish that PAI-1 expression is induced as a consequence of a direct contact with endothelial cells, coculture experiments were performed. PAI-1 mRNA was induced exclusively in fibroblasts (L-cells) contacting endothelial cell (LE-II) colonies. Reporter gene constructs driven by a PAI-1 promoter and stably transfected into L-cells were used to establish that both mouse and rat PAI-1 promoters mediate apposition-dependent regulation. This mode of PAI-1 regulation is not mediated by plasmin, as an identical spatial pattern of expression was detected in cocultures treated with plasmin inhibitors. Because endothelial cells may establish direct contacts with fibroblasts only during angiogenesis, we propose that focal induction of PAI-1 at the site of heterotypic cell contacts provides a mechanism to negate excessive pericellular proteolysis associated with endothelial cell invasion. © 1998 by The American Society of Hematology.

Involvement of RAGE, NADPH Oxidase, and Ras/Raf-1 Pathway in Glycated LDL-Induced Expression of Heat Shock Factor-1 and Plasminogen Activator Inhibitor-1 in Vascular Endothelial Cells

Endocrinology ◽  
2010 ◽  
Vol 151 (9) ◽  
pp. 4455-4466 ◽  
Author(s):  
Ganesh V. Sangle ◽  
Ruozhi Zhao ◽  
Tooru M. Mizuno ◽  
Garry X. Shen
Keyword(s):  
Vascular Endothelial Cells ◽  
Plasminogen Activator Inhibitor ◽  
Heat Shock Factor 1 ◽  
Vascular Endothelial ◽  
Diabetic Mice ◽  
Plasminogen Activator Inhibitor 1 ◽  
Small Interference Rna ◽  
Activator Inhibitor ◽  
Pai 1 ◽  
Interference Rna

Atherothrombotic cardiovascular diseases are the predominant causes of mortality of diabetic patients. Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor for fibrinolysis, and it is also implicated in inflammation and tissue remodeling. Increased levels of PAI-1 and glycated low-density lipoprotein (glyLDL) were detected in patients with diabetes. Previous studies in our laboratory demonstrated that heat shock factor-1 (HSF1) is involved in glyLDL-induced PAI-1 overproduction in vascular endothelial cells (EC). The present study investigated transmembrane signaling mechanisms involved in glyLDL-induced HSF1 and PAI-1 up-regulation in cultured human vascular EC and streptozotocin-induced diabetic mice. Receptor for advanced glycation end products (RAGE) antibody prevented glyLDL-induced increase in the abundance of PAI-1 in EC. GlyLDL significantly increased the translocation of V-Ha-Ras Harvey rat sarcoma viral oncogene homologue (H-Ras) from cytoplasm to membrane compared with LDL. Farnesyltransferase inhibitor-277 or small interference RNA against H-Ras inhibited glyLDL-induced increases in HSF1 and PAI-1 in EC. Treatment with diphenyleneiodonium, a nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor, blocked glyLDL-induced translocation of H-Ras, elevated abundances of HSF1 and PAI-1 in EC, and increased release of hydrogen peroxide from EC. Small interference RNA for p22phox prevented glyLDL-induced expression of NOX2, HSF1, and PAI-1 in EC. GlyLDL significantly increased V-raf-1 murine leukemia viral oncogene homolog 1 (Raf-1) phosphorylation. Treatment with Raf-1 inhibitor blocked glyLDL-induced increase of PAI-1 mRNA in EC. The levels of RAGE, H-Ras, NOX4, HSF1, and PAI-1 were increased in hearts of streptozotocin-diabetic mice and positively correlated with plasma glucose. The results suggest that RAGE, NOX, and H-Ras/Raf-1 are implicated in the up-regulation of HSF1 or PAI-1 in vascular EC under diabetes-associated metabolic stress.

Apposition-Dependent Induction of Plasminogen Activator Inhibitor Type 1 Expression: A Mechanism for Balancing Pericellular Proteolysis During Angiogenesis

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 939-945
Author(s):  
Eran Bacharach ◽  
Ahuva Itin ◽  
Eli Keshet
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
L Cells ◽  
Inhibitor Type ◽  
Activator Inhibitor Type ◽  
Pericellular Proteolysis ◽  
Activator Inhibitor ◽  
Pai 1

Plasminogen-activator inhibitor type I (PAI-1), the primary inhibitor of urinary-type plasminogen activator, is thought to play an important role in the control of stroma invasion by both endothelial and tumor cells. Using an in vitro angiogenesis model of capillary extension through a preformed monolayer, in conjunction with in situ hybridization analysis, we showed that PAI-1 mRNA is specifically induced in cells juxtaposed next to elongating sprouts. To further establish that PAI-1 expression is induced as a consequence of a direct contact with endothelial cells, coculture experiments were performed. PAI-1 mRNA was induced exclusively in fibroblasts (L-cells) contacting endothelial cell (LE-II) colonies. Reporter gene constructs driven by a PAI-1 promoter and stably transfected into L-cells were used to establish that both mouse and rat PAI-1 promoters mediate apposition-dependent regulation. This mode of PAI-1 regulation is not mediated by plasmin, as an identical spatial pattern of expression was detected in cocultures treated with plasmin inhibitors. Because endothelial cells may establish direct contacts with fibroblasts only during angiogenesis, we propose that focal induction of PAI-1 at the site of heterotypic cell contacts provides a mechanism to negate excessive pericellular proteolysis associated with endothelial cell invasion. © 1998 by The American Society of Hematology.

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