Transgenic mice overexpressing human Bcl-2 are resistant to hepatic ischemia and reperfusion

• Published in: Journal of hepatology 2002-02, Vol.36 (2), p.218-225
• Main Authors: SELZNER, Markus, RÜDIGER, Hannes A, SELZNER, Nazia, THOMAS, Dennis W, SINDRAM, David, CLAVIEN, Pierre-Alain
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - physiology; Biological and medical sciences; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression; Hepatocytes - pathology; Humans; Immunity, Innate - genetics; In Situ Nick-End Labeling; Liver - pathology; Liver - physiopathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Other diseases. Semiology; Proto-Oncogene Proteins c-bcl-2 - genetics; Reperfusion Injury - mortality; Reperfusion Injury - pathology; Reperfusion Injury - physiopathology
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/s0168-8278(01)00259-8

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. 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. 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. 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).