Transgenic mice overexpressing human Bcl-2 are resistant to hepatic ischemia and reperfusion.
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).
Selzner
Markus
M
Laboratory of Liver Transplantation and Hepatobiliary Surgery, Department of Visceral Surgery and Transplantation, University of Zürich, 8091 Zürich, Switzerland.
Rüdiger
Hannes A
HA
Selzner
Nazia
N
Thomas
Dennis W
DW
Sindram
David
D
Clavien
Pierre Alain
PA
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*
D019253:Proto-Oncogene Proteins c-bcl-2