title: Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR-α/sirtuin 1/PGC-1α pathway.
abstract: OBJECTIVE
  Atrial metabolic remodelling is critical for the process of atrial fibrillation (AF). The PPAR-α/sirtuin 1 /PPAR co-activator α (PGC-1α) pathway plays an important role in maintaining energy metabolism. However, the effect of the PPAR-α agonist fenofibrate on AF is unclear. Therefore, the aim of this study was to determine the effect of fenofibrate on atrial metabolic remodelling in AF and explore its possible mechanisms of action.
  
  
  METHODS
  The expression of metabolic proteins was examined in the left atria of AF patients. Thirty-two rabbits were divided into sham, AF (pacing with 600 beats·min(-1) for 1 week), fenofibrate treated (pretreated with fenofibrate before pacing) and fenofibrate alone treated (for 2 weeks) groups. HL-1 cells were subjected to rapid pacing in the presence or absence of fenofibrate, the PPAR-α antagonist GW6471 or sirtuin 1-specific inhibitor EX527. Metabolic factors, circulating biochemical metabolites, atrial electrophysiology, adenine nucleotide levels and accumulation of glycogen and lipid droplets were assessed.
  
  
  RESULTS
  The PPAR-α/sirtuin 1/PGC-1α pathway was significantly inhibited in AF patients and in the rabbit/HL-1 cell models, resulting in a reduction of key downstream metabolic factors; this effect was significantly restored by fenofibrate. Fenofibrate prevented the alterations in circulating biochemical metabolites, reduced the level of adenine nucleotides and accumulation of glycogen and lipid droplets, reversed the shortened atrial effective refractory period and increased risk of AF.
  
  
  CONCLUSIONS
  Fenofibrate inhibited atrial metabolic remodelling in AF by regulating the PPAR-α/sirtuin 1/PGC-1α pathway. The present study may provide a novel therapeutic strategy for AF.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Guang-Zhong
authors.initials: GZ
authors.lastname: Liu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Hou
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Peng-Zhou
authors.initials: PZ
authors.lastname: Hang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Guan-Qi
authors.initials: GQ
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Cardiac Diseases and Heart, Failure of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Jing-Mei
authors.initials: JM
authors.lastname: Dong
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Shi
authors.affiliation: Centre for Drug Safety Evaluation, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China.
authors.forename: Yong-Wu
authors.initials: YW
authors.lastname: Liu
authors.affiliation: Department of Morphology, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China.
authors.forename: Jing-Hua
authors.initials: JH
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Cardiac Diseases and Heart, Failure of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Zeng-Xiang
authors.initials: ZX
authors.lastname: Dong
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Cheng-Chuang
authors.initials: CC
authors.lastname: Zhan
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.|Key Laboratory of Cardiac Diseases and Heart, Failure of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.|Key Laboratory of Cardiac Diseases and Heart, Failure of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Li
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D064752:Atrial Remodeling / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology; D002460:Cell Line; D011345:Fenofibrate / Q000494:pharmacology* / Q000627:therapeutic use; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D011817:Rabbits; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; C449302:GW 6471; D010080:Oxazoles; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014443:Tyrosine; D056564:Sirtuin 1; D011345:Fenofibrate