title: Glucagon-like peptide-1 receptor agonist liraglutide inhibits endothelin-1 in endothelial cell by repressing nuclear factor-kappa B activation.
abstract: OBJECTIVE
  The increase in endothelin-1 (ET-1) and the decrease in endothelial nitric oxide synthase (eNOS) both induce vasoconstriction and lead to molecular changes associated with diabetes mellitus and atherosclerosis. Glucagon-like peptide-1 (GLP-1) activation stimulates insulin secretion and may prevent atherosclerosis by increasing eNOS synthesis. However, there is paucity of information on the effect of GLP-1 activation on ET-1 expression. This study was conducted to address this issue.
  
  
  RESULTS
  Human umbilical vein endothelial cells (HUVECs) were incubated with different concentrations of liraglutide, a GLP-1 agonist, and the expression of ET-1 and eNOS and activity of NF-κB were measured. Liraglutide, in a concentration-dependent manner, was observed to promote eNOS expression and to inhibit ET-1 expression both at mRNA and protein levels. Liraglutide also inhibited NF-κB phosphorylation and its translocation from cytoplasm to the nucleus. To ascertain the role of NF-κB activation in the altered expression of ET-1 and eNOS, we treated HUVECs with phorbol 12-myristate 13-acetate (PMA). PMA activated NF-κB and reversed the effects of liraglutide on eNOS and ET-1 expression. The effects of PMA on eNOS and ET-1 expression were reproduced in experiments wherein cells were treated with TNF-α. Further, we measured the generation of IL-6, apowerful pro-inflammatory molecule released by endothelial cells, as a measure of cellular function. PMA increased IL-6 generation, and this effect was blocked by liraglutide.
  
  
  CONCLUSIONS
  Our observations suggest liraglutide suppresses ET-1 expression by inhibiting the phosphorylation of NF-κB. This mechanism may underlie the potential anti-atherosclerotic effects of GLP-1 agonists. Of note, these effects of liraglutide were seen in an in vitro setting wherein cellular glucose concentrations were elevated.
authors: Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors: Yao
authors: Y
authors: Dai
authors: Jawahar L
authors: JL
authors: Mehta
authors: Mingwei
authors: M
authors: Chen
mesh_terms: D002478:Cells, Cultured; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D000069450:Liraglutide; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D018027:Receptors, Glucagon / Q000819:agonists* / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D015850:Interleukin-6; D016328:NF-kappa B; D018027:Receptors, Glucagon; C016658:phorbolol myristate acetate; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D013755:Tetradecanoylphorbol Acetate