title: Fibroblast growth factor 21 protects against high glucose induced cellular damage and dysfunction of endothelial nitric-oxide synthase in endothelial cells.
abstract: OBJECTIVE
  Fibroblast growth factor 21 (FGF21) is a powerful endocrine hormone modulating glucose and lipid metabolism and represents a promising drug for type 2 diabetes. The present study was to determine the effect of FGF21 on high glucose-induced damage and dysfunction in endothelial cells.
  
  
  METHODS
  The protein expression of β-klotho was examined in human umbilical vein endothelial cell (HUVECs) using immunofluorescence and Western blotting. HUVECs were cultured in medium with normal glucose (NG), high glucose (HG) and HG + FGF21 (30 nM). Cell viability, migration, reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase, nitric oxide (NO) production, intracellular cyclic guanosine monophosphate (cGMP) and endothelial nitric oxide synthase (eNOS) phosphorylation at Ser-1177/Ser-633 sites were measured.
  
  
  RESULTS
  β-klotho, the anchor protein of FGF21, is expressed in HUVECs. Administration of FGF21 prevented HG-induced impairment of cell viability, migration, oxidant stress, NO production and intracellular cGMP levels in HUVECs. FGF21 also rescued HG-induced decrease of eNOS phosphorylation at Ser-1177 and Ser-633. HG and FGF21 had no effects on eNOS phosphorylation at Ser-617 and Thr-495. Inhibition of AMP-activated protein kinase (AMPK), but not Akt or Ca(2+)/calmodulin-dependent protein kinase II, abolished the protective effect of FGF21 on eNOS phosphorylation at Ser-1177. The protective effect of FGF21 on eNOS phosphorylation at Ser-633 was also abolished by inhibition of AMPK but not by Akt or cAMP-dependent protein kinase A.
  
  
  CONCLUSIONS
  Our results provide the first evidence that FGF21 protects against high glucose induced cell damage and eNOS dysfunction in an AMPK-dependent manner in HUVECs, and suggest that FGF21 may be a promoting therapeutic agent for vascular complications in diabetes.
authors.affiliation: Department of Geriatrics, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Wang
authors.forename: Shuang-Shuang
authors.initials: SS
authors.lastname: Song
authors.forename: Hang
authors.initials: H
authors.lastname: Xiao
authors.forename: Pan
authors.initials: P
authors.lastname: Gao
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Li
authors.forename: Liang-Yi
authors.initials: LY
authors.lastname: Si
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D015153:Blotting, Western; D042783:Endothelial Cells / Q000201:enzymology*; D005346:Fibroblast Growth Factors / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000008:administration & dosage / Q000633:toxicity*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D000090265:Klotho Proteins; D008315:Malondialdehyde / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C538995:KLB protein, human; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; C414620:fibroblast growth factor 21; D008315:Malondialdehyde; D005346:Fibroblast Growth Factors; D052250:Nitric Oxide Synthase Type III; D000263:Adenylate Kinase; D000090265:Klotho Proteins; D005947:Glucose