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¹ Australian Centre for Blood Diseases, Monash University, 6th Floor Burnett Tower, 89 Commercial Road, Prahran 3181, Melbourne, Victoria, Australia² Eastern Clinical Research Unit, Biotechnology Division, Monash University, 6th Floor Burnett Tower, 89 Commercial Road, Prahran 3181, Melbourne, Victoria, Australia³ Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark⁴ 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) administration attenuates endothelial cell dysfunction in diabetic patients and inhibits tumour necrosis factor (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.

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