Aldehyde Dehydrogenase-2 Deficiency Aggravates Cardiac Dysfunction Elicited by Endoplasmic Reticulum Stress Induction

Abstract

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) has been characterized as an important mediator of endogenous cytoprotection in the heart. This study was designed to examine the role of ALDH2 knockout (KO) in the regulation of cardiac function after endoplasmic reticulum (ER) stress. Wild-type (WT) and ALDH2 KO mice were subjected to a tunicamycin challenge, and the echocardiographic property was examined. Protein levels of six items-78 kDa glucose-regulated protein (GRP78), phosphorylation of eukaryotic initiation factor 2 subunit α (p-eIF2α), CCAAT/enhancer-binding protein homologous protein (CHOP), phosphorylation of Akt, p47 phox nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and 4-hydroxynonenal-were determined by using Western blot analysis. Cytotoxicity and apoptosis were estimated using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay and caspase-3 activity, respectively. ALDH2 deficiency exacerbated cardiac contractile dysfunction and promoted ER stress after ER stress induction, manifested by the changes of ejection fraction and fractional shortening. In vitro study revealed that tunicamycin significantly upregulated the levels of GRP78, p-eIF2α, CHOP, p47 phox NADPH oxidase and 4-hydroxynonenal, which was exacerbated by ALDH2 knockdown and abolished by ALDH2 overexpression, respectively. Overexpression of ALDH2 abrogated tunicamycin-induced dephosphorylation Akt. Inhibition of phosphatidylinositol 3-kinase using LY294002 did not affect ALDH2-conferred protection against ER stress, although LY294002 reversed the antiapoptotic action of ALDH2 associated with p47 phox NADPH oxidase. These results suggest a pivotal role of ALDH2 in the regulation of ER stress and ER stress-induced apoptosis. The protective role of ALDH2 against ER stress-induced cell death was probably mediated by Akt via a p47 phox NADPH oxidase-dependent manner. These findings indicate the critical role of ALDH2 in the pathogenesis of ER stress in heart disease.

Increased expression of microRNA-378a-5p in acute ethanol exposure of rat cardiomyocytes

“…Alcohol intake can increase the acetaldehyde level significantly (Balbo and Brooks 2015;Brooks and Theruvathu 2005). In principle, the observed ALDH2 reduction may exacerbate cell death stimulated by ethanol, as an anti-apoptotic action of ALDH2 associated with p47 (phox) NADPH oxidase has been implied by the studies using ALDH2 knockout mice (Liao et al 2012). …”

Endoplasmic Reticulum Stress Regulates the Innate Immunity Critical Transcription Factor IRF3

“…AEBSF also inhibits reactive oxygen species generation by NADPH (70). Tg, Tm, and ER stress related to cholesterol loading have all been found to induce oxidative stress via NADPH (71)(72)(73). Reactive oxygen species potentiate IRF3 activation (74).…”

Aldehyde dehydrogenase 2 activation ameliorates CCl4‐induced chronic liver fibrosis in mice by up‐regulating Nrf2/HO‐1 antioxidant pathway

“…Adult male C57BL/6 (8‐week old) was purchased from Shanghai Animal Administration Centre (Shanghai, China) and ALDH2 knockout mice with the same genetic background were reproduced as described previously . For the wild‐type (WT) and ALDH2 knockout (KO) group, age‐ and sex‐matched mice received twice‐weekly intraperitoneal injections with CCl 4 (0.32 mL/kg; Sigma‐Aldrich, St. Louis, MO, USA) for 8 weeks.…”