title: Transgenic mice overexpressing human Bcl-2 are resistant to hepatic ischemia and reperfusion.
abstract: OBJECTIVE
  Apoptosis is a key mechanism of reperfusion injury in the ischemic liver. The apoptotic pathway is highly regulated by anti-apoptotic factors, such as Bcl-2. We evaluated the effect of Bcl-2 overexpression on apoptosis and the activation of the apoptotic cascade after hepatic ischemia and reperfusion.
  
  
  METHODS
  Ninety minutes of ischemia and reperfusion was performed in Bcl-2 transgenic and non-transgenic mice. Bcl-2 overexpression was determined by immunohistochemistry and Western blot. Liver injury was determined by aspartate aminotransferase (AST), Tunel test and the activation of the apoptotic cascade and animal survival.
  
  
  RESULTS
  Bcl-2 overexpression was present in all hepatocytes and non-parenchymal liver cells in transgenic mice. Bcl-2 overexpression resulted in significant decreased AST levels after ischemic injury, and complete inhibition of apoptosis. After 90 min of total hepatic ischemia all control mice died, while four transgenic mice survived permanently. Bcl-2 overexpression was associated with inhibition of caspase 3 activation after reperfusion and increased baseline levels of cytoplasmic cytochrome c, caspase 3, and a reduction of Bcl-x(L) production.
  
  
  CONCLUSIONS
  Bcl-2 overexpression protects against ischemic injury by inhibiting apoptosis. Extensive overproduction of Bcl-2 is associated with a compensatory increase of baseline levels of cytoplasmic cytochrome c and caspase 3, and a deletion of Bcl-x(L).
authors.affiliation: Laboratory of Liver Transplantation and Hepatobiliary Surgery, Department of Visceral Surgery and Transplantation, University of Zürich, 8091 Zürich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Selzner
authors.forename: Hannes A
authors.initials: HA
authors.lastname: Rüdiger
authors.forename: Nazia
authors.initials: N
authors.lastname: Selzner
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Thomas
authors.forename: David
authors.initials: D
authors.lastname: Sindram
authors.forename: Pierre Alain
authors.initials: PA
authors.lastname: Clavien
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015870:Gene Expression; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D015427:Reperfusion Injury / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2