title: Decreased expression of mitochondrial aldehyde dehydrogenase-2 induces liver injury via activation of the mitogen-activated protein kinase pathway.
abstract: The aim of this study was to determine the role of ALDH2 in the injury of liver from brain-dead donors. Using brain-dead rabbit model and hypoxia model, levels of ALDH2 and apoptosis in tissues and cell lines were determined by Western blot, flow cytometry (FCM), and transferase (TdT)-mediated biotin-16-dUTP nick-end labeling (TUNEL) assays. After the expression of ALDH2 during hypoxia had been inhibited or activated, the accumulations of 4-hydroxynonenal (4-HNE) and molecules involved in mitogen-activated protein kinase (MAPK) signaling pathway were analyzed using ELISA kit and Western blot. The low expression of phosphorylated ALDH2 in liver was time-dependent in the brain-dead rabbit model. Immunohistochemistry showed ALDH2 was primarily located in endothelial, and the rates of cell apoptosis in the donation after brain-death (DBD) rabbit groups significantly increased with time. Following the treatment of inhibitor of ALDH2, daidzein, in combination with hypoxia for 8 h, the apoptosis rate and the levels of 4-HNE, P-JNK, and cleaved caspase-3 significantly increased in contrast to that in hypoxic HUVECs; however, they all decreased after treatment with Alda-1 and hypoxia compared with that in hypoxic HUVECs (P < 0.05). Instead, the levels of P-P38, P-ERK, P-JNK, and cleaved caspase-3 decreased and the ratio of bcl-2/bax increased with ad-ALDH2 (10(6) pfu/ml) in combination with hypoxia for 8 h, which significantly alleviated in contrast to that in hypoxic HUVECs. We found low expression of ALDH2 and high rates of apoptosis in the livers of brain-dead donor rabbits. Furthermore, decreased ALDH2 led to apoptosis in HUVECs through MAPK pathway.
authors.affiliation: Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China.
authors.forename: Zibiao
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China.
authors.forename: Shaojun
authors.initials: S
authors.lastname: Ye
authors.affiliation: Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Jianghan District Center for Disease Control and Prevention, Wuhan Hubei, China.
authors.forename: Lianxi
authors.initials: L
authors.lastname: Wu
authors.affiliation: Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Fan
authors.affiliation: Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: The 3rd Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, Changsha, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China.
authors.forename: Huanglei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China.
authors.forename: Mingyun
authors.initials: M
authors.lastname: Chen
authors.affiliation: Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Yan
authors.affiliation: Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Massachusetts General Hospital, Department of Urology, Harvard Medical School, Boston, MA, USA.
authors.forename: Dicken Shiu-Chung
authors.initials: DS
authors.lastname: Ko
authors.affiliation: Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Wuhan University, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Hubei Key Laboratory of Medical Technology on Transplantation, Wuhan Hubei, China.|The 3rd Xiangya Hospital of Central South University, Research Center of National Health Ministry on Transplantation Medicine Engineering and Technology, Changsha, China.
authors.forename: Qifa
authors.initials: Q
authors.lastname: Ye
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D001926:Brain Death; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006084:Graft Rejection; D006085:Graft Survival; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D016031:Liver Transplantation / Q000009:adverse effects / Q000379:methods; D008297:Male; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011817:Rabbits; D011897:Random Allocation; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; D000444:Aldehyde Dehydrogenase; D020928:Mitogen-Activated Protein Kinases
keywords: apoptosis; brain death; mitochondrial aldehyde dehydrogenase 2; mitogen-activated protein kinase pathway