title: Remote Liver Ischemic Preconditioning Protects against Sudden Cardiac Death via an ERK/GSK-3β-Dependent Mechanism.
abstract: BACKGROUND
  Preconditioning stimuli conducted in remote organs can protect the heart against subsequent ischemic injury, but effects on arrhythmogenesis and sudden cardiac death (SCD) are unclear. Here, we investigated the effect of remote liver ischemia preconditioning (RLIPC) on ischemia/reperfusion (I/R)-induced cardiac arrhythmia and sudden cardiac death (SCD) in vivo, and determined the potential role of ERK/GSK-3βsignaling.
  
  
  RESULTS
  Male Sprague Dawley rats were randomized to sham-operated, control, or RLIPC groups. RLIPC was induced by alternating four 5-minute cycles of liver ischemia with 5-minute intermittent reperfusions. To investigate I/R-induced arrhythmogenesis, hearts in each group were subsequently subjected to 5-minute left main coronary artery ligation followed by 20-minute reperfusion. RLIPC reduced post-I/R ventricular arrhythmias, and decreased the incidence of SCD >threefold. RLIPC increased phosphorylation of cardiac ERK1/2, and GSK-3β Ser9 but not Tyr216 post-I/R injury. Inhibition of either GSK-3β (with SB216763) or ERK1/2 (with U0126) abolished RLIPC-induced antiarrhythmic activity and GSK-3β Ser9 and ERK1/2 phosphorylation, leaving GSK-3β Tyr216 phosphorylation unchanged.
  
  
  CONCLUSIONS
  RLIPC exerts a powerful antiarrhythmic effect and reduces predisposition to post-IR SCD. The underlying mechanism of RLIPC cardioprotection against I/R-induced early arrhythmogenesis may involve ERK1/2/GSK-3β Ser9-dependent pathways.
authors: Laboratory of Anesthesiology & Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors: Zhaoyang
authors: Z
authors: Hu
authors: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi, China.
authors: Sheng
authors: S
authors: Hu
authors: Laboratory of Anesthesiology & Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors: Shuai
authors: S
authors: Yang
authors: Laboratory of Anesthesiology & Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors: Mou
authors: M
authors: Chen
authors: Laboratory of Anesthesiology & Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors: Ping
authors: P
authors: Zhang
authors: Laboratory of Anesthesiology & Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors: Jin
authors: J
authors: Liu
authors: Bioelectricity Laboratory, Dept. of Pharmacology and Dept. of Physiology and Biophysics, School of Medicine, University of California Irvine, Irvine, California, United States of America.
authors: Geoffrey W
authors: GW
authors: Abbott
mesh_terms: D000818:Animals; D016757:Death, Sudden, Cardiac / Q000517:prevention & control*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D019194:Ischemic Preconditioning; D008099:Liver / Q000098:blood supply*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000071679:Glycogen Synthase Kinase 3 beta; D048049:Extracellular Signal-Regulated MAP Kinases