Activation of aldehyde dehydrogenase 2 slows down the progression of atherosclerosis via attenuation of ER stress and apoptosis in smooth muscle cells

Authors: Mei-yan YANG1,2, Ya-bin WANG1, Bo HAN2, Bo YANG1, Yu-wei QIANG1, Yan ZHANG1, Zhao WANG1, Xu HUANG1, Jie LIU1, Yundai CHEN1, Jun REN3, Feng CAO1, Yong XU1
1 Department of Cardiology, State Key Laboratory of Kidney Disease, Chinese PLA General Hospital, Beijing 100853, China
2 Department of Internal Medicine, Beijing Changping Hospital, Beijing 102200, China
3 Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA
Corresponding to: Jun REN:, Feng CAO:, Yong XU:,
DOI: 10.1038/aps.2017.81
Received: 17 December 2016
Accepted: 19 May 2017
Advance online: 31 August 2017


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.
Keywords: atherosclerosis; aldehyde dehydrogenase 2; Alda-1; daidzin; endoplasmic reticulum stress; apoptosis; smooth muscle cells