title: The glucagon-like peptide 1 analog liraglutide reduces TNF-α-induced oxidative stress and inflammation in endothelial cells.
abstract: OBJECTIVE
  Glucagon-like peptide 1 (GLP-1), one of the incretin hormones, has been reported to increase positive inotropic activity in cardiac myocytes and protect against myocardial injury. However, the effects upon endothelial cells and the mechanisms involved are not fully understood. We assessed the hypothesis that GLP-1 has protective effects against inflammation and oxidative stress on human endothelial cells.
  
  
  RESULTS
  The effects of the GLP-1 analog liraglutide upon TNF-α-induced injury of the human umbilical vein endothelial cells (HUVECs) were evaluated. First, ROS induced by TNF-α was measured by staining with CM-H(2)DCFDA. Intracellular ROS production of HUVECs was significantly decreased in a dose-dependent manner until 30 nM while liraglutide inhibited the induction of gp91(phox) and p22(phox), subunit of NADPH oxidase, by TNF-α. In addition, protein levels of SOD-2, catalase and GPx were significantly increased by liraglutide. Second, rapid translocation of PKC-α into the membrane following TNF-α was evident. Liraglutide significantly inhibited this very rapid TNF-α-induced translocation of PKC-α into membrane at 2.5 min. Third, liraglutide significantly inhibited NF-κB activation and upregulated I-κB family while phosphorylation of IKK-α/β, which is upstream of NF-κB signaling, was also downregulated after 15 min of TNF-α treatment. Finally, liraglutide inhibited apoptosis of HUVEC and expression of Pentraxin-3 induced by TNF-α.
  
  
  CONCLUSIONS
  Liraglutide exerts marked anti-oxidative and anti-inflammatory effects on endothelial cells with inhibition of PKC-α, NADPH oxidase, NF-κB signaling and upregulation of protective anti-oxidative enzymes.
authors.affiliation: Saga University Faculty of Medicine Department of Cardiovascular and Renal Medicine, 5-1-1 Nabeshima, Saga 849-8501, Japan. junoyama@cc.saga-u.ac.jp
authors.forename: Aya
authors.initials: A
authors.lastname: Shiraki
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Oyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Komoda
authors.forename: Machiko
authors.initials: M
authors.lastname: Asaka
authors.forename: Aiko
authors.initials: A
authors.lastname: Komatsu
authors.forename: Masashi
authors.initials: M
authors.lastname: Sakuma
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Kodama
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Norihiko
authors.initials: N
authors.lastname: Kotooka
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Hirase
authors.forename: Koichi
authors.initials: K
authors.lastname: Node
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002097:C-Reactive Protein / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D000069450:Liraglutide; D008562:Membrane Glycoproteins / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D000683:Serum Amyloid P-Component / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000099153:Pentraxins; D000099156:Superoxide Dismutase 2
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002097:C-Reactive Protein; D002374:Catalase; D052216:Glucagon-Like Peptide 1; D005979:Glutathione Peroxidase; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D000069450:Liraglutide; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D016328:NF-kappa B; D051571:Protein Kinase C-alpha; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D000683:Serum Amyloid P-Component; D013482:Superoxide Dismutase; D014409:Tumor Necrosis Factor-alpha; D000099153:Pentraxins; D000099156:Superoxide Dismutase 2; C056558:CYBB protein, human; C086986:CYBA protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496628:PRKCA protein, human