title: Rapamycin protection of livers from ischemia and reperfusion injury is dependent on both autophagy induction and mammalian target of rapamycin complex 2-Akt activation.
abstract: BACKGROUND
  Although rapamycin (RPM) have been studied extensively in ischemia models, its functional mechanisms remains to be defined.
  
  
  METHODS
  We determined how RPM impacted the pathogenesis of ischemia-reperfusion injury (IRI) in a murine liver partial warm ischemia model, with emphasis on its regulation of hepatocyte death.
  
  
  RESULTS
  Rapamycin protected livers from IRI in the presence of fully developed liver inflammatory immune response. Rapamycin enhanced liver autophagy induction at the reperfusion stage. Dual mammalian (mechanistic) target of rapamycin (mTOR)1/2 inhibitor Torin 1, despite its ability to induced autophagy, failed to protect livers from IRI. The treatment with RPM, but not Torin 1, resulted in the enhanced activation of the mTORC2-Akt signaling pathway activation in livers after reperfusion. Inactivation of Akt by Triciribine abolished the liver protective effect of RPM. The differential cytoprotective effect of RPM and Torin 1 was confirmed in vitro in hepatocyte cultures. Rapamycin, but not Trin 1, protected hepatocytes from stress and tumor necrosis factor-α induced cell death; and inhibition of autophagy by chloroquine or Akt by Triciribine abolished RPM-mediated cytoprotection.
  
  
  CONCLUSIONS
  Rapamycin protected livers from IRI by both autophagy and mTORC2-Akt activation mechanisms.
authors.affiliation: 1 Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA. 2 Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Zhu
authors.forename: Tianfei
authors.initials: T
authors.lastname: Lu
authors.forename: Shi
authors.initials: S
authors.lastname: Yue
authors.forename: Xiuda
authors.initials: X
authors.lastname: Shen
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhai
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D019610:Cytoprotection; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D009287:Naphthyridines / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D052096:Warm Ischemia
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D046912:Multiprotein Complexes; D009287:Naphthyridines; D020011:Protective Agents; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus