title: Roles of Sestrin2 and Ribosomal Protein S6 in Transient Global Ischemia-Induced Hippocampal Neuronal Injury.
abstract: Recent studies suggested that sestrin2 is a crucial modulator for the production of reactive oxygen species (ROS). In addition, sestrin2 may also regulate ribosomal protein S6 (RpS6), a molecule important for protein synthesis, through the effect of mammalian target of rapamycin (mTOR) complex that is pivotal for longevity. However, the roles of sestrin2 in cerebral ischemia, in which oxidative stress is one of the major pathogenic mechanisms, are still less understood. In this study, we hypothesized that sestrin2 may protect hippocampal CA1 neurons against transient global ischemia (TGI)-induced apoptosis by regulating RpS6 phosphorylation in rats. We found that sestrin2 expression was progressively increased in the hippocampal CA1 subfield 1-48 h after TGI, reaching the maximal level at 24 h, and declined thereafter. Further, an increased extent of RpS6 phosphorylation, but not total RpS6 protein level, was observed in the hippocampal CA1 subfield after TGI. The sestrin2 siRNA, which substantially blocked the expression of TGI-induced sestrin2, also abolished RpS6 phosphorylation. TGI with reperfusion may induce oxidative stress with the resultant formation of 8-hydroxy-deoxyguanosine (8-OHdG). We found that sestrin2 siRNA further augmented the formation of 8-OHdG induced by TGI with reperfusion for 4 h. Consistently, sestrin2 siRNA also enhanced apoptosis induced by TGI with reperfusion for 48 h based on the analysis of DNA fragmentation by agarose gel electrophoresis, DNA fragmentation sandwich ELISA, and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Together these findings indicated that TGI-induced sestrin2 expression contributed to RpS6 phosphorylation and neuroprotection against ischemic injury in the hippocampal CA1 subfield.
authors.affiliation: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan. jyang@adm.cgmh.org.tw.|Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan. jyang@adm.cgmh.org.tw.|Department of Neurology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 833, Taiwan. jyang@adm.cgmh.org.tw.
authors.forename: Yao-Chung
authors.initials: YC
authors.lastname: Chuang
authors.affiliation: Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan. jyang@adm.cgmh.org.tw.
authors.forename: Jenq-Lin
authors.initials: JL
authors.lastname: Yang
authors.affiliation: Institute of Brain Science, National Yang-Ming University, Taipei 112, Taiwan. diyang@ym.edu.tw.
authors.forename: Ding-I
authors.initials: DI
authors.lastname: Yang
authors.affiliation: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan. tklin@adm.cgmh.org.tw.
authors.forename: Tsu-Kung
authors.initials: TK
authors.lastname: Lin
authors.affiliation: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan. cwliou@ms22.hinet.net.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Liou
authors.affiliation: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan. chensd@adm.cgmh.org.tw.|Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan. chensd@adm.cgmh.org.tw.
authors.forename: Shang-Der
authors.initials: SD
authors.lastname: Chen
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D020868:Gene Silencing; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D017966:Pyramidal Cells / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D038601:Ribosomal Protein S6 / Q000235:genetics / Q000378:metabolism*; D000084622:Sestrins
chemical_list: D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D038601:Ribosomal Protein S6; C583887:Sesn2 protein, rat; D000084622:Sestrins
keywords: hippocampus CA1 neurons; oxidative stress; ribosomal protein S6; sestrin2; transient global ischemia