title: Inhibition of glycogen synthase kinase 3 ameliorates liver ischemia/reperfusion injury via an energy-dependent mitochondrial mechanism.
abstract: OBJECTIVE
  The mechanisms of glycogen synthase kinase-3 (GSK-3)-mediated cytoprotection during liver ischemia/reperfusion (I/R) remain controversial, particularly in older organs. This study explores the role and potential mechanisms of GSK-3 in young and aging livers.
  
  
  METHODS
  A rodent partial warm I/R model was used to evaluate the therapeutic potential of GSK-3 modulation during hepatic I/R in young and aging Sprague-Dawley rats.
  
  
  RESULTS
  GSK-3 inhibition through IPC or SB216763 (SB21) preconditioning protected young rats from I/R-induced liver injury. This protection was absent in old animals but could be restored by glucose infusion prior to the I/R insult. The protection conferred by GSK-3 inhibition depended on mitochondrial metabolism regulation. Indeed, the inhibition of GSK-3 suppressed mitochondrial permeability transition pore (MPTP) opening, triggering mitohormesis in young animals, whereas insufficient fuel suppressed mitochondrial metabolism and inactivated the GSK-3-related protection in old animals. SB21 and glucose reactivated the mitochondrial F0F1-ATPase and subsequent protective cascades in the senescent liver. These effects were antagonized by an ATPase inhibitor and by an MPTP opener.
  
  
  CONCLUSIONS
  The protection conferred by GSK-3 inhibition during hepatic I/R insult is energy dependent, particularly in senescent livers. These findings demonstrate a key role for GSK-3-related mitochondrial energy homeostasis, which may shed new light on the clinical use of GSK-3 inhibitors to protect liver function in surgical settings, particularly for older patients.
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qiufeng
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Yuan
authors.affiliation: National Key Laboratory of Medical Immunology and Department of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: National Key Laboratory of Medical Immunology and Department of Immunology, Second Military Medical University, Shanghai 200433, China. Electronic address: wangqx@immunol.org.
authors.forename: Quanxing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai 200433, China. Electronic address: miaomy@163.com.
authors.forename: Mingyong
authors.initials: M
authors.lastname: Miao
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200433, China. Electronic address: shixueyin1128@163.com.
authors.forename: Xueyin
authors.initials: X
authors.lastname: Shi
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D019610:Cytoprotection; D004734:Energy Metabolism / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D019194:Ischemic Preconditioning / Q000379:methods*; D008301:Maleimides / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology; D006180:Proton-Translocating ATPases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control
chemical_list: D007211:Indoles; D008301:Maleimides; D020011:Protective Agents; C417521:SB 216763; D038362:Glycogen Synthase Kinase 3; D006180:Proton-Translocating ATPases
keywords: Energy metabolism; Ischemia/reperfusion injury; Mitochondria; Reactive oxygen; Signal transduction