Alda-1 attenuation of binge alcohol-caused atrial arrhythmias through a novel mechanism of suppressed c-Jun N-terminal Kinase-2 activity

Jiajie Yan; Saugat Khanal; Yuanyuan Cao; Nikola Ricchiuti; Alma Nani; S R Wayne Chen; Michael Fill; Dan J Bare; Xun Ai

doi:10.1016/j.yjmcc.2024.10.003

Alda-1 attenuation of binge alcohol-caused atrial arrhythmias through a novel mechanism of suppressed c-Jun N-terminal Kinase-2 activity

J Mol Cell Cardiol. 2024 Oct 10:S0022-2828(24)00164-0. doi: 10.1016/j.yjmcc.2024.10.003. Online ahead of print.

Authors

Jiajie Yan¹, Saugat Khanal¹, Yuanyuan Cao¹, Nikola Ricchiuti¹, Alma Nani², S R Wayne Chen³, Michael Fill², Dan J Bare¹, Xun Ai⁴

Affiliations

¹ Department of Physiology and Cell Biology, College of Medicine/Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
² Department of Physiology & Biophysics, Rush University Medical Center, Chicago, IL, USA.
³ Department of Physiology and Pharmacology, the Libin Cardiovascular Institute, University of Calgary, Calgary, Canada.
⁴ Department of Physiology and Cell Biology, College of Medicine/Wexner Medical Center, The Ohio State University, Columbus, OH, USA. Electronic address: ai.87@osu.edu.

PMID: 39395657
DOI: 10.1016/j.yjmcc.2024.10.003

Abstract

Holiday Heart Syndrome (HHS) is caused by excessive binge alcohol consumption, and atrial fibrillation (AF) is the most common arrhythmia among HHS patients. AF is associated with substantial morbidity and mortality, making its prevention and treatment of high clinical interest. This study defines the anti-AF action of Alda-1 (an established cardioprotective agent) and the underlying mechanisms of the action in our well-characterized HHS and cellular models. We found that Alda-1 effectively eliminated binge alcohol-evoked Ca²⁺ triggered activities (Ca²⁺ waves, prolonged Ca²⁺ transient diastolic decay) and arrhythmia inducibility in intact mouse atria. We then demonstrated that alcohol impaired human RyR2 channels (isolated from organ donors' hearts). The functional role of alcohol-caused RyR2 channel dysfunction in Ca²⁺ triggered arrhythmic activities was evidenced in a unique transgenic mouse model with a loss-of-function mutation (RyR2^E4872Q+/-). Alda-1 is known to activate aldehyde dehydrogenase 2 (ALDH2), a key enzyme in alcohol detoxification. However, we found an increased level of ALDH2 and a preserved normal balance of pro- vs anti-apoptotic signaling in binge alcohol exposed hearts and H9c2 differentiated myocytes, which suggests that the link of alcohol-ALDH2-apoptosis is unlikely to be a key factor leading to binge alcohol-evoked arrhythmogenicity. We have previously reported that binge alcohol-activated stress response kinase JNK2 causatively drives Ca²⁺-triggered atrial arrhythmogenicity. Here, we found that JNK2-specific inhibition in either isolated human RyR2 channels or intact mouse atria abolished alcohol-evoked RyR2 channel dysfunction and Ca²⁺ triggered arrhythmic activities, suggesting a strong alcohol-JNK2-RyR2 interaction in atrial arrhythmogenicity. Furthermore, we revealed, for the first time, that Alda-1 suppresses JNK2 (but not JNK1) enzyme activity independently of ALDH2, which in turn alleviates binge alcohol-evoked Ca²⁺ triggered atrial arrhythmogenesis. Our findings provide novel mechanistic insights into the anti-arrhythmic action of Alda-1 and suggest that Alda-1 represents a potential preventative agent for AF management for HHS patients.

Keywords: Alda-1; Atrial arrhythmias; C-Jun N-terminal kinase-2; Calcium transients; Cardiac protection; Holiday heart syndrome.