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 aldehyde dehydrogenase-2 knockout (KO) in the pathogenesis of heart underwent endoplasmic reticulum (ER) stress induction. Wild-type (WT) and ALDH2 KO mice were subjected to tunicamycin challenge and echocardiographic examination was performed. Protein levels of GRP78, p-eIF2α, CHOP, phosphorylation of Akt, p47phox NADPH oxidase, and 4-hydroxynonenal were determined by Western blot analysis. Cytotoxicity and apoptosis were estimated by MTT assay and caspase-3 activity respectively. ALDH2 deficiency exacerbated cardiac dysfunction and increased the protein levels of ER stress markers after ER stress induction characterized by the changes of ejection fraction and fractional shorting, when compared with WT mice. In vitro, tunicamycin significantly increased in the levels of GRP78, p-eIF2, CHOP and p47phox NADPH oxidase, which was exacerbated by ALDH2 knockdown and abolished by ALDH2 overexpression. Overexpression of ALDH2 abrogated tunicamycin-induced dephosphorylation of Akt. Inhibition of PI3-K with LY294002 did not negatively affect the inhibition of ER stress markers conferred by ALDH2, but reversed the anti-apoptotic role of ALDH2, which may be associated with p47phox NADPH oxidase. These results suggest that ALDH2 was implicated in the regulation of ER stress and ER stress-induced apoptosis. The protective role of ALDH2 against cell death induced by ER stress was probably mediated by Akt signaling via p47phox NADPH oxidase. These findings indicate a critical role of ALDH2 in the pathogenesis of ER stress in heart disease.
Critical role of mitochondrial aldehyde dehydrogenase 2 in acrolein sequestering in rat spinal cord injury
