title: Remote ischemic preconditioning protects against liver ischemia-reperfusion injury via heme oxygenase-1-induced autophagy.
abstract: BACKGROUND
  Growing evidence has linked autophagy to a protective role of preconditioning in liver ischemia/reperfusion (IR). Heme oxygenase-1 (HO-1) is essential in limiting inflammation and preventing the apoptotic response to IR. We previously demonstrated that HO-1 is up-regulated in liver graft after remote ischemic preconditioning (RIPC). The aim of this study was to confirm that RIPC protects against IR via HO-1-mediated autophagy.
  
  
  METHODS
  RIPC was performed with regional ischemia of limbs before liver ischemia, and HO-1 activity was inhibited pre-operation. Autophagy was assessed by the expression of light chain 3-II (LC3-II). The HO-1/extracellular signal-related kinase (ERK)/p38/mitogen-activated protein kinase (MAPK) pathway was detected in an autophagy model and mineral oil-induced IR in vitro.
  
  
  RESULTS
  In liver IR, the expression of LC3-II peaked 12-24 h after IR, and the ultrastructure revealed abundant autophagosomes in hepatocytes after IR. Autophagy was inhibited when HO-1 was inactivated, which we believe resulted in the aggravation of liver IR injury (IRI) in vivo. Hemin-induced autophagy also protected rat hepatocytes from IRI in vitro, which was abrogated by HO-1 siRNA. Phosphorylation of p38-MAPK and ERK1/2 was up-regulated in hemin-pretreated liver cells and down-regulated after treatment with HO-1 siRNA.
  
  
  CONCLUSIONS
  RIPC may protect the liver from IRI by induction of HO-1/p38-MAPK-dependent autophagy.
authors.affiliation: Department of Oncological Surgery 2, Xuzhou City Central Hospital, The Affiliated Hospital of the Southeast University Medical School (Xuzhou), The Tumor Research Institute of the Southeast University (Xuzhou), Xuzhou, Jiangsu Province, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Gastroenterology II, Xuzhou City Central Hospital, The Affiliated Hospital of the Southeast University Medical School (Xuzhou), Xuzhou, Jiangsu Province, China.
authors.forename: Xuanxuan
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Department of General Surgery, Yancheng First People's Hospital, Yancheng, Jiangsu Province, China.
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Changjun
authors.initials: C
authors.lastname: Huang
authors.affiliation: Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Jiao
authors.affiliation: Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Xuehao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Xiangcheng
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D004789:Enzyme Activation; D015870:Gene Expression; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019194:Ischemic Preconditioning; D008099:Liver / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D011524:Protoporphyrins; D034741:RNA, Small Interfering; C017803:zinc protoporphyrin; D051547:Heme Oxygenase-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases