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¹ Australian Centre for Blood Diseases and ² Eastern Clinical Research Unit, Biotechnology Division, Monash University, 6th Floor Burnett Tower, 89 Commercial Road, Prahran 3181, Melbourne, Victoria, Australia ³ Department of Diabetes and Endocrinology, 4th Floor Clive Ward Centre, Box Hill Hospital, Arnold Street, Box Hill 3128, Melbourne, Victoria, Australia

(Correspondence should be addressed to A E Dear; Email: anthony.dear{at}med.monash.edu.au)

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- (TNF-). GLP-1 also inhibited the effect of TNF- on a reporter gene construct harbouring the proximal PAI-1 promoter. In addition, GLP-1 attenuated TNF--mediated induction of Nur77 mRNA and TNF--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--mediated induction of Akt phosphorylation. Taken together, these observations suggest that GLP-1 inhibits TNF--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.