title: Mitochondrial aldehyde dehydrogenase obliterates insulin resistance-induced cardiac dysfunction through deacetylation of PGC-1α.
abstract: Insulin resistance contributes to the high prevalence of type 2 diabetes mellitus, leading to cardiac anomalies. Emerging evidence depicts a pivotal role for mitochondrial injury in oxidative metabolism and insulin resistance. Mitochondrial aldehyde dehydrogenase (ALDH2) is one of metabolic enzymes detoxifying aldehydes although its role in insulin resistance remains elusive. This study was designed to evaluate the impact of ALDH2 overexpression on insulin resistance-induced myocardial damage and mechanisms involved with a focus on autophagy. Wild-type (WT) and transgenic mice overexpressing ALDH2 were fed sucrose or starch diet for 8 weeks and cardiac function and intracellular Ca2+ handling were assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate Akt, heme oxygenase-1 (HO-1), PGC-1α and Sirt-3. Our data revealed that sucrose intake provoked insulin resistance and compromised fractional shortening, cardiomyocyte function and intracellular Ca2+ handling (p < 0.05) along with unaltered cardiomyocyte size (p > 0.05), mitochondrial injury (elevated ROS generation, suppressed NAD+ and aconitase activity, p < 0.05 for all), the effect of which was ablated by ALDH2. In vitro incubation of the ALDH2 activator Alda-1, the Sirt3 activator oroxylin A and the histone acetyltransferase inhibitor CPTH2 rescued insulin resistance-induced changes in aconitase activity and cardiomyocyte function (p < 0.05). Inhibiting Sirt3 deacetylase using 5-amino-2-(4-aminophenyl) benzoxazole negated Alda-1-induced cardioprotective effects. Taken together, our data suggest that ALDH2 serves as an indispensable cardioprotective factor against insulin resistance-induced cardiomyopathy with a mechanism possibly associated with facilitation of the Sirt3-dependent PGC-1α deacetylation.
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.|Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.|Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.|Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, USA.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology*; D004452:Echocardiography; D004734:Energy Metabolism; D005951:Glucose Tolerance Test; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D009243:NAD; D051547:Heme Oxygenase-1; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D051057:Proto-Oncogene Proteins c-akt; D000154:Aconitate Hydratase; D002118:Calcium
keywords: ALDH2; PGC-1; Pathology Section; Sirt3; insulin resistance; sucrose