title: Mindin deficiency protects the liver against ischemia/reperfusion injury.
abstract: OBJECTIVE
  Hepatic ischemia/reperfusion (I/R) injury often occurs during liver surgery and may cause liver failure. Our previous studies revealed that Mindin is involved in the pathogenesis of ischemic stroke. However, the function of Mindin in hepatic I/R injury remains unknown.
  
  
  METHODS
  Partial hepatic warm ischemia was induced in parallel in global Mindin knockout mice (Mindin KO), hepatocyte-specific Mindin knockdown mice, hepatocyte-specific Mindin transgenic mice (Mindin TG), myeloid cell-specific Mindin TG mice (LysM-Mindin TG), and their corresponding controls, followed by reperfusion. Hepatic histology, serum aminotransferase, inflammatory cytokines, and hepatocyte apoptosis and proliferation were examined to assess liver injury. The molecular mechanisms of Mindin function were explored in vivo and in vitro.
  
  
  RESULTS
  Mindin KO and hepatocyte-specific Mindin knockdown mice exhibited less liver damage than controls, with smaller necrotic areas and lower serum transaminase levels. Mindin deficiency significantly suppressed inflammatory cell infiltration, cytokine and chemokine production, and hepatocyte apoptosis, but increased hepatocyte proliferation following hepatic I/R injury. In contrast, the opposite pathological and biochemical changes were observed in hepatocyte-specific Mindin TG mice, whereas no significant changes in liver damage were found in LysM-Mindin TG mice compared to non-transgenic controls. Mechanistically, Akt signaling was activated in livers of Mindin KO mice but was suppressed in Mindin TG mice. Most importantly, Akt inhibitor treatment blocked the protective effect of Mindin deficiency on hepatic I/R injury.
  
  
  CONCLUSIONS
  Mindin is a novel modulator of hepatic I/R injury through regulating inflammatory responses, as well as hepatocyte apoptosis and proliferation via inactivation of the Akt signaling pathway.
authors.affiliation: Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Pi-Xiao
authors.initials: PX
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Zhu
authors.affiliation: Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China.
authors.forename: Yibao
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Song
authors.initials: S
authors.lastname: Tian
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China.
authors.forename: Xueyong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China. Electronic address: lihl@whu.edu.cn.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000172:deficiency* / Q000235:genetics*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016326:Extracellular Matrix Proteins; C121491:mindin; D012313:RNA
keywords: Akt; Cell death; Hepatic ischemia/reperfusion; Inflammation; Mindin; Regeneration