Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, P.R. China; Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, Hubei, P.R. China; Hubei Key Laboratory of Cardiology, Wuhan, 430060, Hubei, P.R. China.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, P.R. China; Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, Hubei, P.R. China; Hubei Key Laboratory of Cardiology, Wuhan, 430060, Hubei, P.R. China.
Toxicology. 2022 Jan 15;465:153055. doi: 10.1016/j.tox.2021.153055. Epub 2021 Dec 3.
Both long-term and short-term alcohol consumption can cause internal homeostasis imbalance, and they have been proved to be related to the initiation and development of atrial fibrillation (AF). Ferroptosis is an iron-dependent form of non-apoptotic oxidative death which also regulate the cell death homeostasis, but whether it involves in AF induced by alcohol consumption remains unclear. Here, we report a study on the effect of ferroptosis on susceptibility to AF at different alcohol consumption frequencies. We divided the mice into single or frequent excessive alcohol consumption group which given sterile drinking water or alcohol by gavage at different frequencies. Meanwhile, the experimental group was given an intraperitoneal injection of ferroptosis inhibitor (Fer-1) before alcohol drinking. It was found that once exposure to 5 g/kg/d frequent excessive alcohol consumption, compared with the single excessive alcohol consumption group, the mice serum non-heme iron concentration, accumulation of iron and oxidative stress reaction in atrial tissues were increased, while the body weight, heart weight and heart weight to tibia length (HW/TL) ratio were decreased. In addition, the inducibility rate of AF increased, while RR interval, effective refractory periods (ERPs) and 90 % action potential duration (APD) shortened, as well as QTc interval prolonged. Furthermore, the protein and mRNA expression levels of GPx4, FTL, FTH1, Kv1.5, Kv2.1, Kv4.3, Cav1.2, Serca2α, p-PLB were down-regulated, while PTGS2 was up-regulated. Most of the changes can be partially or completely reversed by Fer-1. These results suggest that frequent excessive alcohol consumption activates ferroptosis and increases the inducibility rate of AF. Nevertheless, inhibition of ferroptosis can balance iron overload disorders and reduce the generation of reactive oxygen species (ROS), eventually decrease the susceptibility to AF. Our results highlight the importance of guidance and warnings for unhealthy alcohol-abuse lifestyle.
长期和短期饮酒均可导致体内内环境失衡，且已证实与心房颤动（AF）的发生和发展有关。铁死亡是一种铁依赖性的非凋亡性氧化死亡形式，它也调节细胞死亡的内稳态，但它是否涉及饮酒引起的 AF 尚不清楚。在这里，我们报告了一项关于铁死亡对不同饮酒频率下 AF 易感性影响的研究。我们将小鼠分为单次或频繁过量饮酒组，分别给予无菌饮用水或灌胃不同频率的酒精。同时，实验组在饮酒前给予铁死亡抑制剂（Fer-1）腹腔注射。结果发现，一旦暴露于 5 g/kg/d 频繁过量饮酒，与单次过量饮酒组相比，小鼠血清非血红素铁浓度、心房组织铁积累和氧化应激反应增加，而体重、心脏重量和心脏重量与胫骨长度（HW/TL）比值降低。此外，AF 的诱发性增加，而 RR 间期、有效不应期（ERPs）和 90%动作电位时程（APD）缩短，以及 QTc 间期延长。此外，GPx4、FTL、FTH1、Kv1.5、Kv2.1、Kv4.3、Cav1.2、Serca2α、p-PLB 的蛋白和 mRNA 表达水平下调，而 PTGS2 上调。Fer-1 可部分或完全逆转大多数变化。这些结果表明，频繁过量饮酒激活铁死亡并增加 AF 的诱发性。然而，抑制铁死亡可以平衡铁过载紊乱并减少活性氧（ROS）的产生，最终降低 AF 的易感性。我们的结果强调了对不健康的酒精滥用生活方式进行指导和警告的重要性。
