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

AbstractBackground

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.

Objectives

The purpose of this study was to detail how JNK promotes binge alcohol-evoked susceptibility to AF.

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 Ca²⁺ activity (Ca²⁺ waves, sarcoplasmic reticulum [SR] Ca²⁺ leakage), and membrane voltage (V_m) and systolic Ca²⁺ release spatiotemporal heterogeneity (t_Vm-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.

Results

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.

Conclusions

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.

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