title: GLP-1-dependent and independent effects and molecular mechanisms of a dipeptidyl peptidase 4 inhibitor in vascular endothelial cells.
abstract: The potential atheroprotective effects of glucagon-like peptide-1 (GLP-1), long-acting GLP-1 analogues and inhibitors of the enzyme dipeptidyl peptidase 4 (DPP-4) are currently the subject of intense research. Recent evidence suggests the effects of DPP-IV inhibitors, may, in-part, be mediated by GLP-1 independent molecular mechanisms. In this report we demonstrate that treatment of human vascular endothelial cells with the DPP-IV inhibitor sitagliptin inhibited tumour necrosis factor alpha (TNFα) induction of plasminogen activator inhibitor type-1 (PAI-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) mRNA and protein expression and that this effect was observed to be both GLP-1-dependent and independent. Importantly we identify a molecular mechanism involving sitagliptin-mediated attenuation of TNFα-mediated induction of NFκB and orphan nuclear receptor NUR77 mRNA expression, also able to be reproduced, in part, independent of GLP-1. Taken together these observations may serve to provide a molecular explanation, involving transcriptional regulation of gene expression, for recent in vivo studies suggesting DPP-IV inhibitors may have novel, GLP-1 independent, effects in acting to attenuate endothelial cell dysfunction and atherogenesis.
authors.affiliation: Eastern Clinical Research Unit, Translational Research Division, Department of Medicine, Australian Centre for Blood Diseases, Monash University, 89 Commercial Rd., Prahran 3181, Melbourne, VIC, Australia.
authors.forename: Yunshan
authors.initials: Y
authors.lastname: Hu
authors.forename: Hu
authors.initials: H
authors.lastname: Y
authors.forename: HongBin
authors.initials: H
authors.lastname: Liu
authors.forename: Liu
authors.initials: L
authors.lastname: Hb
authors.forename: Richard W
authors.initials: RW
authors.lastname: Simpson
authors.forename: Simpson
authors.initials: S
authors.lastname: Rw
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Dear
authors.forename: Dear
authors.initials: D
authors.lastname: Ae
mesh_terms: D002460:Cell Line; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011719:Pyrazines / Q000494:pharmacology; D000068900:Sitagliptin Phosphate; D015533:Transcriptional Activation; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D016328:NF-kappa B; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D017395:Plasminogen Activator Inhibitor 1; D011719:Pyrazines; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate