Role of Stress Kinase JNK in Binge Alcohol-Evoked Atrial Arrhythmia

Jiajie Yan; Justin K. Thomson; Weiwei Zhao; Xianlong Gao; Fei Huang; Biyi Chen; Qingrong Liang; Long-Sheng Song; Michael Fill; Xun Ai

doi:10.1016/j.jacc.2018.01.060

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Role of Stress Kinase JNK in Binge Alcohol-Evoked Atrial Arrhythmia

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Role of Stress Kinase JNK in Binge Alcohol-Evoked Atrial Arrhythmia

Jiajie Yan, Justin K. Thomson, Weiwei Zhao, Xianlong Gao, Fei Huang, Biyi Chen, Qingrong Liang, Long-Sheng Song, Michael Fill and Xun Ai

Journal of the American College of Cardiology, Vol.71(13), pp.1459-1470

04/03/2018

DOI: 10.1016/j.jacc.2018.01.060

PMCID: PMC5903584

PMID: 29598867

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Abstract

Excessive binge alcohol drinking has acute cardiac arrhythmogenic effects, including promotion of atrial fibrillation (AF), which underlies “Holiday Heart Syndrome.” The mechanism that couples binge alcohol abuse with AF susceptibility remains unclear. We previously reported stress-activated c-Jun N-terminal kinase (JNK) signaling contributes to AF development. This is interesting because JNK is implicated in alcohol-caused organ malfunction beyond the heart. The purpose of this study was to detail how JNK promotes binge alcohol-evoked susceptibility to AF. The authors found binge alcohol-exposure leads to activated JNK, specifically JNK2. Furthermore, binge alcohol induces AF, higher incidence of diastolic intracellular Ca2+ activity (Ca2+ waves, sarcoplasmic reticulum [SR] Ca2+ leakage), and membrane voltage (Vm) and systolic Ca2+ release spatiotemporal heterogeneity (ΔtVm-Ca). These changes were completely eliminated by JNK inhibition both in vivo and in vitro. Calmodulin kinase II (CaMKII) is a proarrhythmic molecule known to drive SR Ca2+ mishandling. The authors report for the first time that binge alcohol activates JNK2, which subsequently phosphorylates the CaMKII protein, enhancing CaMKII-driven SR Ca2+ mishandling. CaMKII inhibition eliminates binge alcohol-evoked arrhythmic activities. Our studies demonstrate that binge alcohol exposure activates JNK2 in atria, which then drives CaMKII activation, prompting aberrant Ca2+ waves and, thus, enhanced susceptibility to atrial arrhythmia. Our results reveal a previously unrecognized form of alcohol-driven kinase-on-kinase proarrhythmic crosstalk. Atrial JNK2 function represents a potential novel therapeutic target to treat and/or prevent AF. [Display omitted]

AF vulnerability

arrhythmic calcium activity

binge alcohol drinking

JNK

kinase inhibition

proarrhythmic calmodulin kinase II

stress-response kinase

Details

Title: Subtitle: Role of Stress Kinase JNK in Binge Alcohol-Evoked Atrial Arrhythmia
Creators: Jiajie Yan - Rush University Medical Center
Justin K. Thomson - Loyola University Chicago
Weiwei Zhao - Rush University Medical Center
Xianlong Gao - Loyola University Chicago
Fei Huang - Rush University Medical Center
Biyi Chen - University of Iowa
Qingrong Liang - New York Institute of Technology College of Osteopathic Medicine
Long-Sheng Song - University of Iowa
Michael Fill - Rush University Medical Center
Xun Ai - Rush University Medical Center
Resource Type: Journal article
Publication Details: Journal of the American College of Cardiology, Vol.71(13), pp.1459-1470
DOI: 10.1016/j.jacc.2018.01.060
PMID: 29598867
PMCID: PMC5903584
NLM abbreviation: J Am Coll Cardiol
ISSN: 0735-1097
eISSN: 1558-3597
Publisher: Elsevier Inc
Language: English
Date published: 04/03/2018
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984293084302771

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