Aldehyde dehydrogenase-2 (ALDH2) ameliorates chronic alcohol ingestion-induced myocardial insulin resistance and endoplasmic reticulum stress

Chronic alcohol intake leads to insulin resistance and alcoholic cardiomyopathy, which appears to be a result of the complex interaction between genes and environment. This study was designed to examine the impact of aldehyde dehydrogenase-2 (ALDH2) transgenic overexpression on alcohol-induced insulin resistance and myocardial injury. ALDH2 transgenic mice were produced using chicken beta-actin promoter. Wild-type FVB and ALDH2 mice were fed a 4% alcohol or control diet for 12 weeks. Cell shortening was evaluated using an edge-detection system. Western blot analysis was used to assess insulin signaling at the levels of receptor, IRS, Akt, GSK-3 beta, the transcription factors Foxo3a, c-Jun amino-terminal kinase (JNK) and c-Jun. Chronic alcohol intake led to glucose intolerance, reduced glucose uptake, cardiac hypertrophy and reduced cell shortening, the effects of which were alleviated by ALDH2. ALDH2 significantly attenuated alcohol-induced decrease in the insulin-stimulated tyrosine phosphorylation and increase in serine phosphorylation of IRS. Phosphorylation of Akt, GSK-3 beta and Foxo3a was reduced following alcohol intake, the effect of which was abrogated by ALDH2. Levels of JNK, c-Jun and their phosphorylation were elevated following chronic alcohol intake, which were obliterated by ALDH2. Transfection of H9C2 myoblast cells with Foxo3a adenovirus mimicked acetaldehyde-induced JNK activation and glucose uptake defect whereas the dominant negative Foxo3a ablated acetaldehyde-elicited insulin insensitivity. In addition, ALDH2 reversed alcohol-induced myocardial ER stress. These data revealed that ALDH2 overexpression antagonizes chronic alcohol intake-induced cardiac insulin insensitivity and contractile defect, possibly via improvement of insulin signaling at the levels of insulin receptor, IRS, Akt, Foxo3a and JNK. (C) 2009 Elsevier Inc. All rights reserved.