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

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

Department of Physiology and Cell Biology, College of Medicine/Wexner Medical Center, The Ohio State University, Columbus, OH, USA. Electronic address:

Published: December 2024

AI Article Synopsis

  • Holiday Heart Syndrome (HHS) is linked to excessive binge drinking, resulting in atrial fibrillation (AF), which poses significant health risks and is of great concern for prevention and treatment.
  • This study explores the beneficial effects of Alda-1, which counteracts alcohol-induced calcium (Ca) abnormalities and arrhythmias in mouse atria and isolated human heart channels, suggesting a protective role in HHS-related AF.
  • Findings reveal that Alda-1 inhibits JNK2 enzyme activity independently of alcohol detoxification pathways, providing insights into a potential therapeutic approach to reduce binge alcohol-related arrhythmogenic effects.

Article 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 Ca triggered activities (Ca waves, prolonged Ca 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 Ca triggered arrhythmic activities was evidenced in a unique transgenic mouse model with a loss-of-function mutation (RyR2). 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 Ca-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 Ca 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 Ca 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.

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Source
http://dx.doi.org/10.1016/j.yjmcc.2024.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664791PMC

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