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Role of Stress Kinase JNK in Binge Alcohol-Evoked Atrial Arrhythmia.
- Source :
-
Journal of the American College of Cardiology [J Am Coll Cardiol] 2018 Apr 03; Vol. 71 (13), pp. 1459-1470. - Publication Year :
- 2018
-
Abstract
- Background: 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.<br />Objectives: The purpose of this study was to detail how JNK promotes binge alcohol-evoked susceptibility to AF.<br />Methods: The authors found binge alcohol-exposure leads to activated JNK, specifically JNK2. Furthermore, binge alcohol induces AF (24- vs. 1.8-Hz burst pacing-induced episodes per attempt per animal), higher incidence of diastolic intracellular Ca <superscript>2+</superscript> activity (Ca <superscript>2+</superscript> waves, sarcoplasmic reticulum [SR] Ca <superscript>2+</superscript> leakage), and membrane voltage (V <subscript>m</subscript> ) and systolic Ca <superscript>2+</superscript> release spatiotemporal heterogeneity (Δt <subscript>Vm-Ca</subscript> ). 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 Ca <superscript>2+</superscript> mishandling.<br />Results: The authors report for the first time that binge alcohol activates JNK2, which subsequently phosphorylates the CaMKII protein, enhancing CaMKII-driven SR Ca <superscript>2+</superscript> mishandling. CaMKII inhibition eliminates binge alcohol-evoked arrhythmic activities.<br />Conclusions: Our studies demonstrate that binge alcohol exposure activates JNK2 in atria, which then drives CaMKII activation, prompting aberrant Ca <superscript>2+</superscript> 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.<br /> (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adult
Aged
Animals
Atrial Fibrillation pathology
Binge Drinking complications
Binge Drinking pathology
Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism
Cells, Cultured
Enzyme Activation drug effects
Enzyme Activation physiology
Ethanol administration & dosage
Female
Humans
Isolated Heart Preparation
Male
Mice
Middle Aged
Rabbits
Atrial Fibrillation chemically induced
Atrial Fibrillation enzymology
Binge Drinking enzymology
Ethanol toxicity
Mitogen-Activated Protein Kinase 9 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-3597
- Volume :
- 71
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Journal of the American College of Cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 29598867
- Full Text :
- https://doi.org/10.1016/j.jacc.2018.01.060