title: A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/- mouse model.
abstract: The glucagon like peptide-1 receptor (GLP-1R) agonist liraglutide attenuates induction of plasminogen activator inhibitor type-1 (PAI-1) and vascular adhesion molecule (VAM) expression in human vascular endothelial cells (hVECs) in vitro and may afford protection against endothelial cell dysfunction (ECD), an early abnormality in diabetic vascular disease. Our study aimed to establish the dependence of the in vitro effects of liraglutide on the GLP-1R and characterise its in vivo effects in a mouse model of ECD. In vitro studies utilised the human vascular endothelial cell line C11-STH and enzyme-linked immunosorbent assays (ELISA) for determination of PAI-1 and VAM expression. In vivo studies of vascular reactivity and immunohistochemical analysis were performed in the ApoE(-/-) mouse model. In vitro studies demonstrated GLP-1R-dependent liraglutide-mediated inhibition of stimulated PAI-1 and VAM expression. In vivo studies demonstrated significant improvement in endothelial function in liraglutide treated mice, a GLP-1R dependent effect. Liraglutide treatment also increased endothelial nitric oxide synthase (eNOS) and reduced intercellular adhesion molecule-1 (ICAM-1) expression in aortic endothelium, an effect again dependent on the GLP-1R. Together these studies identify in vivo protection, by the GLP-1R agonist liraglutide, against ECD and provide a potential molecular mechanism responsible for these effects.
authors.affiliation: Department of Pharmacology, Monash University, Australia.
authors.forename: Tracey
authors.initials: T
authors.lastname: Gaspari
authors.forename: HongBin
authors.initials: H
authors.lastname: Liu
authors.forename: Iresha
authors.initials: I
authors.lastname: Welungoda
authors.forename: Yunshan
authors.initials: Y
authors.lastname: Hu
authors.forename: Robert E
authors.initials: RE
authors.lastname: Widdop
authors.forename: Lotte B
authors.initials: LB
authors.lastname: Knudsen
authors.forename: Richard W
authors.initials: RW
authors.lastname: Simpson
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Dear
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D002461:Cell Line, Transformed; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D000069450:Liraglutide; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D016328:NF-kappa B; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D018027:Receptors, Glucagon; C051321:SERPINE1 protein, human; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D014665:Vasodilator Agents; D018799:Intercellular Adhesion Molecule-1; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases