Department of Cardiology, State Key Laboratory of Kidney Disease, Chinese PLA General Hospital, Beijing 100853, China.
Department of Internal Medicine, Beijing Changping Hospital, Beijing 102200, China.
Acta Pharmacol Sin. 2018 Jan;39(1):48-58. doi: 10.1038/aps.2017.81. Epub 2017 Aug 31.
Aldehyde dehydrogenase 2 (ALDH2) is a key mitochondrial enzyme in the metabolism of aldehydes and may have beneficial cardiovascular effects for conditions such as cardiac hypertrophy, heart failure, myocardial I/R injury, reperfusion, arrhythmia, coronary heart disease and atherosclerosis. In this study we investigated the role of ALDH2 in the progression of atherosclerosis and the underlying mechanisms, with a focus on endoplasmic reticulum (ER) stress. A clinical study was performed in 248 patients with coronary heart disease. The patients were divided into two groups according to their ALDH2 genotype. Baseline clinical characteristics and coronary angiography were recorded, and the coronary artery Gensini score was calculated. Serum levels of 4-hydroxy-2-nonenal (4-HNE) were detected. The clinical study revealed that the mutant ALDH2 genotype was an independent risk factor for coronary heart disease. ALDH2 gene polymorphism is closely associated with atherosclerosis and the severity of coronary artery stenosis. Serum levels of 4-HNE were significantly higher in patients with the mutant ALDH2 genotype than in patients with the wild-type ALDH2 genotype. As an in vitro model of atherosclerosis, rat smooth muscle cells (SMCs) were treated with oxygenized low-density lipoprotein (ox-LDL), which significantly elevated the levels of ER markers glucose-regulated protein78 (GRP78), protein kinase R-like ER kinase (PERK), phosphorylated eukaryotic translation initiation factor α subunit (p-eIF2α), activating transcription factor-4 (ATF-4), CEBP homologous protein (CHOP) and 4-HNE in the cells. All the ox-LDL-induced responses were significantly attenuated in the presence of Alda-1 (an ALDH2 activating agent), and accentuated in the presence of daidzin (an ALDH2 inhibitor). Furthermore, pretreatment with ALDH2 activator Alda-1 significantly decreased ox-LDL-induced apoptosis. Similarly, overexpression of ALDH2 protected SMCs against ox-LDL-induced ER stress as well as ER stress-induced apoptosis. These findings suggest that ALDH2 may slow the progression of atherosclerosis via the attenuation of ER stress and apoptosis in smooth muscle cells.
乙醛脱氢酶 2（ALDH2）是醛类代谢中的一种关键线粒体酶，可能对心脏肥大、心力衰竭、心肌 I/R 损伤、再灌注、心律失常、冠心病和动脉粥样硬化等疾病具有有益的心血管作用。在这项研究中，我们研究了 ALDH2 在动脉粥样硬化进展中的作用及其潜在机制，重点关注内质网（ER）应激。对 248 例冠心病患者进行了一项临床研究。根据 ALDH2 基因型将患者分为两组。记录基线临床特征和冠状动脉造影，并计算冠状动脉 Gensini 评分。检测血清 4-羟基-2-壬烯醛（4-HNE）水平。临床研究表明，突变型 ALDH2 基因型是冠心病的独立危险因素。ALDH2 基因多态性与动脉粥样硬化及冠状动脉狭窄程度密切相关。突变型 ALDH2 基因型患者血清 4-HNE 水平明显高于野生型 ALDH2 基因型患者。作为动脉粥样硬化的体外模型，用氧化型低密度脂蛋白（ox-LDL）处理大鼠平滑肌细胞（SMCs），可显著升高内质网标志物葡萄糖调节蛋白 78（GRP78）、蛋白激酶 R 样内质网激酶（PERK）、磷酸化真核翻译起始因子 2α 亚单位（p-eIF2α）、激活转录因子 4（ATF-4）、CEBP 同源蛋白（CHOP）和 4-HNE 的水平。在存在 Alda-1（ALDH2 激活剂）的情况下，所有 ox-LDL 诱导的反应均明显减弱，而在存在大豆苷元（ALDH2 抑制剂）的情况下则明显增强。此外，ALDH2 激活剂 Alda-1 的预处理可显著减少 ox-LDL 诱导的细胞凋亡。同样，ALDH2 的过表达可保护 SMCs 免受 ox-LDL 诱导的内质网应激以及内质网应激诱导的细胞凋亡。这些发现表明，ALDH2 可能通过减轻平滑肌细胞内质网应激和凋亡来减缓动脉粥样硬化的进展。
