AKT and ERK1/2 activation via remote ischemic preconditioning prevents Kcne2-dependent sudden cardiac death.

Zhaoyang Hu,Geoffrey W Abbott,Leng Zhou,Xin Tian,Jin Liu

doi:10.14814/phy2.13957

Zhaoyang Hu, Geoffrey W Abbott + Show 3 more

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https://doi.org/10.14814/phy2.13957

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Abstract

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.

Highlights

Sudden cardiac death (SCD), the major cause of natural death leads to the loss of an estimated 325,000 adult lives in the U.S each year
KCNE2, one of ~25 genes recognized to associate with risk of cardiac arrhythmia, encodes a single transmembrane domain potassium channel ancillary (b) subunit named KCNE2, or MinK-related peptide 1 (MiRP1) (Abbott et al 1999)
To explore the role of Kcne2 deletion on remote ischemic preconditioning (RIPC)-induced antiventricular arrhythmias, all Kcne2+/+ and Kcne2-/mice with or without RIPC stimulus were exposed to a 10-min left main coronary ligation followed by 20-min reperfusion

Summary

Introduction

Sudden cardiac death (SCD), the major cause of natural death leads to the loss of an estimated 325,000 adult lives in the U.S each year. Most sudden cardiac deaths in young people are caused by an inherited cardiac arrhythmia syndrome, often traceable to a single gene defect, in the absence of detectable structural or functional cardiac abnormality prior to SCD (Fishman et al 2010; George 2013). KCNE2, one of ~25 genes recognized to associate with risk of cardiac arrhythmia, encodes a single transmembrane domain potassium channel ancillary (b) subunit named KCNE2, or MinK-related peptide 1 (MiRP1) (Abbott et al 1999). A majority of cardiac arrhythmia cases associated with human KCNE2 sequence variants involve QT prolongation and probably require superimposition of environmental factors such as QT-prolonging drugs (Abbott et al 1999; Sesti et al 2000; Gordon et al 2008; Abbott 2015). KCNE2 forms heteromeric ion channel complexes with a wide variety of voltage-gated potassium (Kv) channel pore-forming a subunits in vitro and in vivo (Abbott et al 1999; Tinel et al 2000a,b; Lewis et al 2004; Roepke et al 2006, 2008, 2011; McCrossan et al 2009; Kanda et al 2011a,b; Abbott 2015), and with a subunits of HCN (pacemaker) channels (Radicke et al 2008; Nawathe et al 2013) and L-type Ca2+ channels (Liu et al 2014)

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