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Am J Physiol Gastrointest Liver Physiol (May 10, 2002). doi:10.1152/ajpgi.00410.2001
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Articles in PresS, published online ahead of print May 10, 2002
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00410.2001
Submitted on September 21, 2001
Accepted on April 20, 2002

Cyclic AMP inhibits bile acid induced apoptosis by blocking caspase activation and cytochrome C release

Cynthia R.L. Webster1*, Paul Usechak1, and M. Sawkat Anwer2

1 Department of Clinical sciences, Tufts Veterinary School, Grafton, MA, USA
2 Department of Biomedical Sciences, Tufts Veterinary School, Grafton, MA, USA

* To whom correspondence should be addressed. E-mail: cynthia.leveille-webster{at}tufts.edu.

We have previously shown that cAMP can protect hepatocytes from bile acid induced apoptosis in cultured rat hepatocytes in a phosphoinositide 3-kinase (PI3K) dependent manner. In these present studies we investigated the mechanisms involved in this anti-apoptotic effect. Hepatocyte apoptosis induced by glychochenodeoxycholate (GCDC) was associated with activation of caspase 3 and caspase 9-like activity, the release of cytochrome C from the mitochondria and translocation of BAX from the cytosol to the mitochondria. Cyclic AMP protected against GCDC induced apoptosis and inhibited caspase 3 and caspase 9-like activity and cytochrome C release in a PI3K dependent manner. Cyclic AMP activated PI3K in p85 immunoprecipitates and resulted in PI3K dependent activation of the survival kinase, Akt. Use of the chemical inhibitor, SB 203508 at a concentration that inhibits Akt phosphorylation partially blocked the protective effect of cAMP against GCDC induced apoptosis. These results suggest that GCDC induced apoptosis in cultured rat hepatocytes proceeds through a caspase dependent intracellular stress pathway and that the survival effect of cAMP is mediated in part by PI3K dependent Akt activation at the level of the mitochondria.




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