AKT and ERK1/2 activation via remote ischemic preconditioning prevents Kcne2-dependent sudden cardiac death.
Zhaoyang Hu, Jin Liu, Leng Zhou, Xin Tian, Geoffrey W Abbott
Author Information
Zhaoyang Hu: Laboratory of Anesthesiology & Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Jin Liu: Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Leng Zhou: Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Xin Tian: Laboratory of Anesthesiology & Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Geoffrey W Abbott: Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California.
Sudden cardiac death (SCD) is the leading global cause of mortality. SCD often arises from cardiac ischemia reperfusion (IR) injury, pathologic sequence variants within ion channel genes, or a combination of the two. Alternative approaches are needed to prevent or ameliorate ventricular arrhythmias linked to SCD. Here, we investigated the efficacy of remote ischemic preconditioning (RIPC) of the limb versus the liver in reducing ventricular arrhythmias in a mouse model of SCD. Mice lacking the Kcne2 gene, which encodes a potassium channel β subunit associated with acquired Long QT syndrome were exposed to IR injury via coronary ligation. This resulted in ventricular arrhythmias in all mice (15/15) and SCD in 5/15 mice during reperfusion. Strikingly, prior RIPC (limb or liver) greatly reduced the incidence and severity of all ventricular arrhythmias and completely prevented SCD. Biochemical and pharmacological analysis demonstrated that RIPC cardioprotection required ERK1/2 and/or AKT phosphorylation. A lack of alteration in GSK-3β phosphorylation suggested against conventional reperfusion injury salvage kinase (RISK) signaling pathway protection. If replicated in human studies, limb RIPC could represent a noninvasive, nonpharmacological approach to limit dangerous ventricular arrhythmias associated with ischemia and/or channelopathy-linked SCD.
