title: Mitochondrial aldehyde dehydrogenase 2 plays protective roles in heart failure after myocardial infarction via suppression of the cytosolic JNK/p53 pathway in mice.
abstract: BACKGROUND
  Increasing evidence suggests a critical role for mitochondrial aldehyde dehydrogenase 2 (ALDH2) in protection against cardiac injuries; however, the downstream cytosolic actions of this enzyme are largely undefined.
  
  
  RESULTS
  Proteomic analysis identified a significant downregulation of mitochondrial ALDH2 in the heart of a rat heart failure model after myocardial infarction. The mechanistic insights underlying ALDH2 action were elucidated using murine models overexpressing ALDH2 or its mutant or with the ablation of the ALDH2 gene (ALDH2 knockout) and neonatal cardiomyocytes undergoing altered expression and activity of ALDH2. Left ventricle dilation and dysfunction and cardiomyocyte death after myocardial infarction were exacerbated in ALDH2-knockout or ALDH2 mutant-overexpressing mice but were significantly attenuated in ALDH2-overexpressing mice. Using an anoxia model of cardiomyocytes with deficiency in ALDH2 activities, we observed prominent cardiomyocyte apoptosis and increased accumulation of the reactive aldehyde 4-hydroxy-2-nonenal (4-HNE). We subsequently examined the impacts of mitochondrial ALDH2 and 4-HNE on the relevant cytosolic protective pathways. Our data documented 4-HNE-stimulated p53 upregulation via the phosphorylation of JNK, accompanying increased cardiomyocyte apoptosis that was attenuated by inhibition of p53. Importantly, elevation of 4-HNE also triggered a reduction of the cytosolic HSP70, further corroborating cytosolic action of the 4-HNE instigated by downregulation of mitochondrial ALDH2.
  
  
  CONCLUSIONS
  Downregulation of ALDH2 in the mitochondria induced an elevation of 4-HNE, leading to cardiomyocyte apoptosis by subsequent inhibition of HSP70, phosphorylation of JNK, and activation of p53. This chain of molecular events took place in both the mitochondria and the cytosol, contributing to the mechanism underlying heart failure.
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (A.S., Y.Z., D.X., H.G., S.W., P.Z., Y.C., J.G.).
authors.forename: Aijun
authors.initials: A
authors.lastname: Sun
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (A.S., Y.Z., D.X., H.G., S.W., P.Z., Y.C., J.G.).
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan (P.W., Y.Q., M.H., T.N., H.T.).
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (A.S., Y.Z., D.X., H.G., S.W., P.Z., Y.C., J.G.).
authors.forename: Danling
authors.initials: D
authors.lastname: Xu
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (A.S., Y.Z., D.X., H.G., S.W., P.Z., Y.C., J.G.).
authors.forename: Hui
authors.initials: H
authors.lastname: Gong
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (A.S., Y.Z., D.X., H.G., S.W., P.Z., Y.C., J.G.).
authors.forename: Shijun
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan (P.W., Y.Q., M.H., T.N., H.T.).
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (A.S., Y.Z., D.X., H.G., S.W., P.Z., Y.C., J.G.).
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (A.S., Y.Z., D.X., H.G., S.W., P.Z., Y.C., J.G.).
authors.forename: Yunqin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan (P.W., Y.Q., M.H., T.N., H.T.).
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Harada
authors.affiliation: Department of Environmental Health, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan (T.I., T.K.).
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Isse
authors.affiliation: Department of Environmental Health, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan (T.I., T.K.).
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: Department of Chemistry and Proteome Research Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, China (H.F., P.Y.).
authors.forename: Huizhi
authors.initials: H
authors.lastname: Fan
authors.affiliation: Department of Chemistry and Proteome Research Center, Institutes of Biomedical Sciences, Fudan University, Shanghai, China (H.F., P.Y.).
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan (H.A., I.K.).
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akazawa
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan (P.W., Y.Q., M.H., T.N., H.T.).
authors.forename: Toshio
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan (P.W., Y.Q., M.H., T.N., H.T.).
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takano
authors.affiliation: Division of Cardiology, Departments of Physiology and Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA (P.P.).
authors.forename: Peipei
authors.initials: P
authors.lastname: Ping
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan (H.A., I.K.).
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China (A.S., Y.Z., D.X., H.G., S.W., P.Z., Y.C., J.G.).
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; D000831:Animals, Newborn; D017209:Apoptosis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation; D009203:Myocardial Infarction / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D016277:Ventricular Function, Left
chemical_list: D000447:Aldehydes; D018840:HSP70 Heat-Shock Proteins; D024101:Mitochondrial Proteins; D016159:Tumor Suppressor Protein p53; C096127:ALDH2 protein, human; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D048031:JNK Mitogen-Activated Protein Kinases; C027576:4-hydroxy-2-nonenal
keywords: ALDH2; apoptosis; heart failure; myocardial infarction; p53