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乙醛脱氢酶 2 通过清除 4-HNE 改善慢性酒精摄入诱导的心房颤动。

Aldehyde Dehydrogenase 2 Ameliorates Chronic Alcohol Consumption-Induced Atrial Fibrillation through Detoxification of 4-HNE.

机构信息

Cardiovascular Division, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, No. 5, Fu-Shin Road, Kwei-Shan, Taoyuan 33305, Taiwan.

Division of Cardiac Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Tao-Yuan 33305, Taiwan.

出版信息

Int J Mol Sci. 2020 Sep 12;21(18):6678. doi: 10.3390/ijms21186678.

DOI:10.3390/ijms21186678
PMID:32932651
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7555032/
Abstract

Aldehyde dehydrogenase 2 (ALDH2) is an enzyme that detoxifies reactive oxygen species (ROS)-generated aldehyde adducts such as 4-hydroxy-trans-2-nonenal (4-HNE). Previous meta-analyses have shown an increase in the risk of atrial fibrillation (AF) in patients with chronic alcohol consumption. , a common dysfunctional polymorphism in the gene, has been linked to an increased risk of cancer and heart disease. We tested the effect of ALDH2 deficiency on alcohol-induced AF in a murine model of chronic-binge ethanol feeding, with knock-in (KI) mice generated by a CRISPR/CAS9 system. In addition, right atrial appendages were obtained from eight patients with AF undergoing open heart surgery. The results showed that burst atrial pacing induced a greater susceptibility to AF in KI mice exposed to chronic ethanol intoxication than in wild-type mice, resulting from a higher degree of 4-HNE accumulation and collagen deposition in their atria. Alda-1 attenuated transforming growth factor beta 1 (TGF-β1) expression and collagen deposition in the atria and reduced AF inducibility. Patients with AF and the allele exhibited greater oxidative stress and substrate remodeling in their atria than non-carriers. In conclusion, ALDH2 deficiency may increase the risk of chronic alcohol and tachypacing-induced AF through the accumulation of 4-HNE and increased ROS production.

摘要

乙醛脱氢酶 2（ALDH2）是一种酶，可解毒活性氧（ROS）生成的醛加合物，如 4-羟基-反式-2-壬烯醛（4-HNE）。先前的荟萃分析表明，慢性酒精摄入患者心房颤动（AF）的风险增加。该基因中的常见功能异常多态性与癌症和心脏病风险增加有关。我们使用 CRISPR/CAS9 系统生成的基因敲入（KI）小鼠在慢性 binge 乙醇喂养的小鼠模型中测试了 ALDH2 缺乏对酒精诱导的 AF 的影响。此外，还从 8 名接受心脏直视手术的 AF 患者的右心耳获得组织样本。结果表明，与野生型小鼠相比，在慢性乙醇中毒暴露的 KI 小鼠中，阵发性心房起搏引起 AF 的易感性更高，这是由于其心房中 4-HNE 积累和胶原沉积程度更高所致。Alda-1 可减弱转化生长因子β 1（TGF-β1）在心房中的表达和胶原沉积，并降低 AF 的诱导性。与非携带者相比，AF 患者和等位基因携带者的心房中表现出更大的氧化应激和底物重塑。总之，ALDH2 缺乏可能通过 4-HNE 积累和增加的 ROS 产生增加慢性酒精和快起搏诱导的 AF 的风险。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5039/7555032/2a4a3202953d/ijms-21-06678-g005.jpg
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