title: HDACi Valproic Acid (VPA) and Suberoylanilide Hydroxamic Acid (SAHA) Delay but Fail to Protect against Warm Hepatic Ischemia-Reperfusion Injury.
abstract: BACKGROUND
  Histone deacetylases (HDAC) catalyze N-terminal deacetylation of lysine-residues on histones and multiple nuclear and cytoplasmic proteins. In various animal models, such as trauma/hemorrhagic shock, ischemic stroke or myocardial infarction, HDAC inhibitor (HDACi) application is cyto- and organoprotective and promotes survival. HDACi reduce stress signaling, cell death and inflammation. Hepatic ischemia-reperfusion (I/R) injury during major liver resection or transplantation increases morbidity and mortality. Assuming protective properties, the aim of this study was to investigate the effect of the HDACi VPA and SAHA on warm hepatic I/R.
  
  
  METHODS
  Male Wistar-Kyoto rats (age: 6-8 weeks) were randomized to VPA, SAHA, vehicle control (pre-) treatment or sham-groups and underwent partial no-flow liver ischemia for 90 minutes with subsequent reperfusion for 6, 12, 24 and 60 hours. Injury and regeneration was quantified by serum AST and ALT levels, by macroscopic aspect and (immuno-) histology. HDACi treatment efficiency, impact on MAPK/SAPK-activation and Hippo-YAP signaling was determined by Western blot.
  
  
  RESULTS
  Treatment with HDACi significantly enhanced hyperacetylation of Histone H3-K9 during I/R, indicative of adequate treatment efficiency. Liver injury, as measured by macroscopic aspect, serum transaminases and histology, was delayed, but not alleviated in VPA and SAHA treated animals. Importantly, tissue destruction was significantly more pronounced with VPA. SAPK-activation (p38 and JNK) was reduced by VPA and SAHA in the early (6h) reperfusion phase, but augmented later on (JNK, 24h). Regeneration appeared enhanced in SAHA and VPA treated animals and was dependent on Hippo-YAP signaling.
  
  
  CONCLUSIONS
  VPA and SAHA delay warm hepatic I/R injury at least in part through modulation of SAPK-activation. However, these HDACi fail to exert organoprotective effects, in this setting. For VPA, belated damage is even aggravated.
authors: Department of Surgery, University Hospital Freiburg, Freiburg, Germany.
authors: Dietrich A
authors: DA
authors: Ruess
authors: Department of Surgery, University Hospital Freiburg, Freiburg, Germany.
authors: Moriz
authors: M
authors: Probst
authors: Department of Surgery, University Hospital Freiburg, Freiburg, Germany.
authors: Goran
authors: G
authors: Marjanovic
authors: Department of Surgery, University Hospital Freiburg, Freiburg, Germany.
authors: Uwe A
authors: UA
authors: Wittel
authors: Department of Surgery, University Hospital Freiburg, Freiburg, Germany.
authors: Ulrich T
authors: UT
authors: Hopt
authors: Department of Surgery, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
authors: Tobias
authors: T
authors: Keck
authors: Department of Surgery, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
authors: Dirk
authors: D
authors: Bausch
mesh_terms: D000107:Acetylation; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D011921:Rats, Inbred WKY; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013696:Temperature; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D056572:Histone Deacetylase Inhibitors; D020011:Protective Agents; D014635:Valproic Acid