title: Resveratrol, a red wine antioxidant, reduces atrial fibrillation susceptibility in the failing heart by PI3K/AKT/eNOS signaling pathway activation.
abstract: BACKGROUND
  Resveratrol has shown benefits in reducing ventricular remodeling and arrhythmias.
  
  
  OBJECTIVE
  This study aimed to assess the therapeutic efficacy of resveratrol in reducing atrial fibrillation (AF) in a heart failure (HF) model and to explore the underlying mechanisms.
  
  
  METHODS
  HF rabbits were created 4 weeks after undergoing coronary ligation. Group 1 (n = 6) was divided into subgroups of (a) normal rabbits, (b) HF sham rabbits, and (c) HF rabbits treated for 1 week with intraperitoneal injections of resveratrol, (d) resveratrol plus wortmannin, or (e) resveratrol plus diphenyleneiodonium chloride (DPI). All rabbits underwent epicardial catheter stimulation. Collagen content, messenger RNA and protein expression in ion channels, and phosphoinositide 3-kinase (PI3K)/AKT/endothelial nitric oxide synthase (eNOS) signaling pathways were studied in left atrial appendage (LAA) preparations. To investigate acute drug effects on left atrial electrophysiology, groups 2 a through 2e (n = 6 per group) were subjected to Langendorff perfusion.
  
  
  RESULTS
  Higher AF inducibility was found in the HF group and groups that were given PI3K and eNOS inhibitors than in the normal and resveratrol-treated groups (P < .001). Histologic analysis of the LAA revealed a decrease in fibrosis in resveratrol-treated groups compared with the HF group (8.95% ± 1.53% vs 26.62% ± 2.19%, P < .001). In real-time polymerase chain reaction analysis, ion channels including Kv1.4, Kv1.5, KvLQT1, Kir2.1, Nav1.5, Cav1.2, NCX, SERCA2a, and phospholamban were upregulated by resveratrol. PI3K, AKT, and eNOS messenger RNA and protein expression were upregulated by resveratrol but were inhibited by the coadministration of wortmannin and DPI.
  
  
  CONCLUSIONS
  Resveratrol decreases left atrial fibrosis and regulates variation in ion channels to reduce AF through the PI3K/AKT/eNOS signaling pathway.
authors: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Eric
authors: E
authors: Chong
authors: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Shih-Lin
authors: SL
authors: Chang
authors: Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Ya-Wen
authors: YW
authors: Hsiao
authors: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Rahul
authors: R
authors: Singhal
authors: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Shuen-Hsin
authors: SH
authors: Liu
authors: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Trung
authors: T
authors: Leha
authors: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Wen-Yu
authors: WY
authors: Lin
authors: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiovascular Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Chiao-Po
authors: CP
authors: Hsu
authors: Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan.
authors: Yao-Chang
authors: YC
authors: Chen
authors: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiovascular Medicine, Department of Internal Medicine, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors: Yi-Jen
authors: YJ
authors: Chen
authors: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiology, Taichung Veterans General Hospital, Taichung, Taiwan.
authors: Tsu-Juey
authors: TJ
authors: Wu
authors: Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa, Japan.
authors: Satoshi
authors: S
authors: Higa
authors: Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan. Electronic address: epsachen@ms41.hinet.net.
authors: Shih-Ann
authors: SA
authors: Chen
mesh_terms: D000730:Androstadienes / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009861:Onium Compounds / Q000378:metabolism / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011817:Rabbits; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000378:metabolism / Q000494:pharmacology; D014920:Wine; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000975:Antioxidants; D004791:Enzyme Inhibitors; D009861:Onium Compounds; D013267:Stilbenes; C007517:diphenyleneiodonium; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077185:Resveratrol; D000077191:Wortmannin
keywords: Atrial fibrillation; Ion channel; Resveratrol; Signaling pathway