title: Aldehyde dehydrogenase 2 ameliorates doxorubicin-induced myocardial dysfunction through detoxification of 4-HNE and suppression of autophagy.
abstract: Mitochondrial aldehyde dehydrogenase (ALDH2) protects against cardiac injury via reducing production of 4-hydroxynonenal (4-HNE) and ROS. This study was designed to examine the impact of ALDH2 on doxorubicin (DOX)-induced cardiomyopathy and mechanisms involved with a focus on autophagy. 4-HNE and autophagic markers were detected by Western blotting in ventricular tissues from normal donors and patients with idiopathic dilated cardiomyopathy. Cardiac function, 4-HNE and levels of autophagic markers were detected in WT, ALDH2 knockout or ALDH2 transfected mice treated with or without DOX. Autophagy regulatory signaling including PI-3K, AMPK and Akt was examined in DOX-treated cardiomyocytes incubated with or without ALDH2 activator Alda-1. DOX-induced myocardial dysfunction, upregulation of 4-HNE and autophagic proteins were further aggravated in ALDH2 knockout mice while they were ameliorated in ALDH2 transfected mice. DOX downregulated Class I and upregulated Class III PI3-kinase, the effect of which was augmented by ALDH2 deletion. Accumulation of 4-HNE and autophagic protein markers in DOX-induced cardiomyocytes was significantly reduced by Alda-1. DOX depressed phosphorylated Akt but not AMPK, the effect was augmented by ALDH2 knockout. The autophagy inhibitor 3-MA attenuated, whereas autophagy inducer rapamycin mimicked DOX-induced cardiomyocyte contractile defects. In addition, rapamycin effectively mitigated Alda-1-offered protective action against DOX-induced cardiomyocyte dysfunction. Our data further revealed downregulated ALDH2 and upregulated autophagy levels in the hearts from patients with dilated cardiomyopathy. Taken together, our findings suggest that inhibition of 4-HNE and autophagy may be a plausible mechanism underscoring ALDH2-offered protection against DOX-induced cardiac defect. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy".
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: sun.aijun@zs-hospital.sh.cn.
authors.forename: Aijun
authors.initials: A
authors.lastname: Sun
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Heart Centre of Zhengzhou Ninth People's Hospital, Zhengzhou, Henan 450000, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Cardiology, Branch of Shanghai First People's Hospital, Shanghai 200050, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Shijun
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Tian
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Hu
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000201:enzymology* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D008658:Inactivation, Metabolic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes; D004317:Doxorubicin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C515029:ALDH2 protein, mouse; C027576:4-hydroxy-2-nonenal
keywords: 4-HNE; ALDH2; Autophagy; Dilated cardiomyopathy; Doxorubicin