title: Proteasome inhibitors protect the steatotic and non-steatotic liver graft against cold ischemia reperfusion injury.
abstract: BACKGROUND
  The dramatic shortage of organs leads to consider the steatotic livers for transplantation although their poor tolerance against ischemia reperfusion injury (IRI). Ubiquitin proteasome system (UPS) inhibition during hypothermia prolongs myocardial graft preservation. The role of UPS in the liver IRI is not fully understood. Bortezomib (BRZ) treatment at non-toxic doses of rats fed alcohol chronically has shown protective effects by increasing liver antioxidant enzymes. We evaluated and compared both proteasome inhibitors BRZ and MG132 in addition to University of Wisconsin preservation solution (UW) at low and non-toxic dose for fatty liver graft protection against cold IRI.
  
  
  METHODS
  Steatotic and non-steatotic livers have been stored in UW enriched with BRZ (100 nM) or MG132 (25 μM), for 24h at 4°C and then subjected to 2-h normothermic reperfusion (37 °C). Liver injury (AST/ALT), hepatic function (bile output; vascular resistance), mitochondrial damage (GLDH), oxidative stress (MDA), nitric oxide (NO) (e-NOS activity; nitrates/nitrites), proteasome chymotrypsin-like activity (ChT), and UPS (19S and 20S5 beta) protein levels have been measured.
  
  
  RESULTS
  ChT was inhibited when BRZ and MG132 were added to UW. Both inhibitors prevented liver injury (AST/ALT), when compared to UW alone. BRZ increased bile production more efficiently than MG132. Only BRZ decreased vascular resistance in fatty livers, which correlated with an increase in NO generation (through e-NOS activation) and AMPK phosphorylation. GLDH and MDA were also prevented by BRZ. In addition, BRZ inhibited adiponectin, IL-1, and TNF alpha, only in steatotic livers.
  
  
  CONCLUSIONS
  MG132 and BRZ, administrated at low and non toxic doses, are very efficient to protect fatty liver grafts against cold IRI. The benefits of BRZ are more effective than those of MG132. This evidenced for the first time the potential use of UPS inhibitors for the preservation of marginal liver grafts and for future applications in the prevention of IRI.
authors.affiliation: Experimental Hepatic Ischemia-Reperfusion Unit, Institut d´Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas, Barcelona, Spain.
authors.forename: Mohamed Amine
authors.initials: MA
authors.lastname: Zaouali
authors.forename: Fawzia
authors.initials: F
authors.lastname: Bardag-Gorce
authors.forename: Teresa
authors.initials: T
authors.lastname: Carbonell
authors.forename: Joan
authors.initials: J
authors.lastname: Oliva
authors.forename: Eirini
authors.initials: E
authors.lastname: Pantazi
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bejaoui
authors.forename: Hassen
authors.initials: H
authors.lastname: Ben Abdennebi
authors.forename: Antoni
authors.initials: A
authors.lastname: Rimola
authors.forename: Joan
authors.initials: J
authors.lastname: Roselló-Catafau
mesh_terms: D052242:Adiponectin / Q000037:antagonists & inhibitors; D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D050377:Cold Ischemia; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects; D005234:Fatty Liver / Q000378:metabolism*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D007976:Leupeptins / Q000494:pharmacology*; D016031:Liver Transplantation / Q000379:methods*; D008930:Mitochondria, Liver / Q000378:metabolism; D009926:Organ Preservation; D019188:Organ Preservation Solutions / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D015427:Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D052242:Adiponectin; D001897:Boronic Acids; D015853:Cysteine Proteinase Inhibitors; D007375:Interleukin-1; D007976:Leupeptins; D019188:Organ Preservation Solutions; D061988:Proteasome Inhibitors; D011719:Pyrazines; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde