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

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.

Urinary cadmium was linearly and positively associated with cardiac infarction/injury score and subclinical myocardial injury in the general population without cardiovascular diseases and chronic kidney disease.

PURPOSE: The study was to investigate the association between urinary cadmium with cardiac infarction/injury score (CIIS) and subclinical myocardial injury (SC-MI) in the general population without cardiovascular diseases (CVDs) and chronic kidney disease (CKD). METHODS: In this large-scale cross-sectional study, we enrolled 4492 individuals without CVDs and CKD from the third National Health and Nutrition Examination Survey. Logistic regression models, linear regression models, subgroup analyses, and restricted cubic spline (RCS) were performed to assess the association between urinary cadmium with CIIS and SC-MI. RESULTS: Participants with SC-MI had higher levels of urinary cadmium compared with those without SC-MI (P < 0.001). In multivariate regression analyses adjusting for all confounding variables, higher levels of urinary cadmium were strongly associated not only with higher risk of SC-MI but also with higher CIIS (P < 0.05). Further subgroup analyses showed that the association between urinary cadmium and SC-MI remained significant in the subgroups of ≥ 50 years, men, smokers, and those without diabetes or hypertension (P < 0.05). Additionally, RCS analysis showed that after adjusting for all confounding factors, urinary cadmium was linearly and positively associated with CIIS and SC-MI (P overall < 0.05, P for nonlinearity > 0.05). CONCLUSION: Urinary cadmium was linearly and positively associated with CIIS and SC-MI in the general population without CVDs and CKD.