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.