title: Aldehyde dehydrogenase 2 deficiency negates chronic low-to-moderate alcohol consumption-induced cardioprotecion possibly via ROS-dependent apoptosis and RIP1/RIP3/MLKL-mediated necroptosis.
abstract: Previous studies evidenced the beneficial effects of low-to-moderate alcohol consumption on cardiovascular system by activation of mitochondrial aldehyde dehydrogenase 2 (ALDH2), a key enzyme metabolizing acetaldehyde to innocuous acetic acid, in diabetic mice. It remains questionable whether people with inactive ALDH2 would also benefit from the drinking habit. Present study was therefore designed to examine the influence of ALDH2 deficiency on low-to-moderate alcohol consumption related myocardial alternations. Wildtype (WT) and ALDH2 knockout (KO) mice were exposed to low-to-moderate alcohol (EtOH) challenge for 6weeks. Cardiac function and cell death related pathways were then measured. Although EtOH exposure did not further improve cardiac function or reduce reactive oxygen species (ROS) levels in WT mice, levels of high density lipoprotein-cholesterol (HDL-c) and expression of heme oxygenase-1 (HO-1) were significantly elevated in WT-EtOH group. However, EtOH exposure in KO mice depressed cardiac function as indicated by reduced left ventricular ejection fraction (EF) and increased myocardial fibrosis deposition as well as the excessive ROS accumulation. Above changes were related to altered cell demise (apoptosis and necroptosis), as shown by upregulated expression of cleaved caspase 9, cleaved caspase 3 and RIP1/RIP3/MLKL cascade. Our results thus suggest that ALDH2 is indispensable for the favorable cardiac effect of low-to-moderate alcohol consumption and ALDH2 deficiency may lead to unexpected cardiac dysfunctions via enhancing myocardial apoptosis and necroptosis.
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Shen
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Cardiology, Shandong University, Jinan 250012, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Cardiology, Kaifeng Central Hospital, Kaifeng 475000, China.
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Cardiology, Huadong Hosptial, Fudan University, Shanghai 200040, China.
authors.forename: Xiaona
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Sun
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Ma
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Institute of Biomedical Science, Fudan University, Shanghai 200032, China; Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China. Electronic address: zhm@tongji.edu.cn.
authors.forename: Hongming
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Institute of Biomedical Science, Fudan University, Shanghai 200032, China.
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Hu
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Institute of Biomedical Science, Fudan University, Shanghai 200032, China. Electronic address: jbge@zs-hospital.sh.cn.
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
authors.affiliation: Shanghai Institute of Cardiovascular Disease, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Institute of Biomedical Science, Fudan University, Shanghai 200032, China. Electronic address: sun.aijun@zs-hospital.sh.cn.
authors.forename: Aijun
authors.initials: A
authors.lastname: Sun
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000172:deficiency*; D000818:Animals; D017209:Apoptosis; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020690:GTPase-Activating Proteins; C490620:Ralbp1 protein, mouse; D017382:Reactive Oxygen Species; C515029:ALDH2 protein, mouse; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C570694:MLKL protein, mouse; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse
keywords: Aldehyde dehydrogenase 2; Apoptosis; Low-to-moderate alcohol consumption; Necroptosis; Reactive oxygen species