Department of Physiology and Cell Biology, College of Medicine/Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
Department of Physiology & Biophysics, Rush University Medical Center, Chicago, IL, USA.
J Mol Cell Cardiol. 2024 Dec;197:11-19. doi: 10.1016/j.yjmcc.2024.10.003. Epub 2024 Oct 11.
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.
假日心脏综合征（HHS）是由过度 binge 饮酒引起的，心房颤动（AF）是 HHS 患者中最常见的心律失常。AF 与大量发病率和死亡率相关，使其预防和治疗具有很高的临床意义。本研究定义了 Alda-1（一种已确立的心脏保护剂）的抗 AF 作用及其在我们特征明确的 HHS 和细胞模型中的作用机制。我们发现 Alda-1 可有效消除 binge 饮酒引起的 Ca 触发活动（Ca 波、延长的 Ca 瞬态舒张衰减）和心律失常易感性在完整的小鼠心房中。然后，我们证明酒精会损害人类 RyR2 通道（从器官捐献者心脏中分离出来）。在具有功能丧失突变（RyR2）的独特转基因小鼠模型中，酒精引起的 RyR2 通道功能障碍在 Ca 触发的心律失常活动中具有功能作用。众所周知，Alda-1 可激活醛脱氢酶 2（ALDH2），这是酒精解毒的关键酶。然而，我们发现在 binge 饮酒暴露的心脏和 H9c2 分化的心肌细胞中，ALDH2 水平升高，促凋亡与抗凋亡信号之间的正常平衡得以维持，这表明酒精-ALDH2-凋亡的联系不太可能是导致 binge 饮酒引起心律失常的关键因素。我们之前曾报道过 binge 饮酒激活应激反应激酶 JNK2，从而导致 Ca 触发的心房心律失常。在这里，我们发现，在分离的人类 RyR2 通道或完整的小鼠心房中特异性抑制 JNK2 可消除酒精引起的 RyR2 通道功能障碍和 Ca 触发的心律失常活动，这表明 JNK2 在心房心律失常中的作用与 RyR2 之间存在强烈的相互作用。此外，我们首次揭示，Alda-1 独立于 ALDH2 抑制 JNK2（但不抑制 JNK1）酶活性，从而减轻 binge 饮酒引起的 Ca 触发的心房心律失常。我们的发现为 Alda-1 的抗心律失常作用提供了新的机制见解，并表明 Alda-1 可能成为 HHS 患者 AF 管理的潜在预防剂。
