Glucagon-like peptide-1 attenuates tumour necrosis factor-alpha-mediated induction of plasminogen [corrected] activator inhibitor-1 expression.
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 plasminogen activator inhibitor type-1 [corrected] (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-alpha (TNF-alpha). GLP-1 also inhibited the effect of TNF-alpha on a reporter gene construct harbouring the proximal PAI-1 promoter. In addition, GLP-1 attenuated TNF-alpha-mediated induction of Nur77 mRNA and TNF-alpha-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-alpha-mediated induction of Akt phosphorylation. Taken together, these observations suggest that GLP-1 inhibits TNF-alpha-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.
Liu
Hongbin
H
Australian Centre for Blood Diseases, Melbourne, Victoria, Australia.
Hu
Yunshan
Y
Simpson
Richard W
RW
Dear
Anthony E
AE
D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D042783:Endothelial Cells / Q000737:chemistry* / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins
D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; D009687:Nuclear Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D052216:Glucagon-Like Peptide 1; D015500:Chloramphenicol O-Acetyltransferase; D051057:Proto-Oncogene Proteins c-akt