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Am J Physiol Gastrointest Liver Physiol 283: G727-G738, 2002. First published May 10, 2002; doi:10.1152/ajpgi.00410.2001
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Vol. 283, Issue 3, G727-G738, September 2002

cAMP inhibits bile acid-induced apoptosis by blocking caspase activation and cytochrome c release

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

Departments of 1 Clinical Science and 2 Biomedical Science, Tufts University School of Veterinary Medicine, North Grafton, Massachusetts 01536

We have previously shown that cAMP protects against bile acid-induced apoptosis in cultured rat hepatocytes in a phosphoinositide 3-kinase (PI3K)-dependent manner. In the present studies, we investigated the mechanisms involved in this anti-apoptotic effect. Hepatocyte apoptosis induced by glycodeoxycholate (GCDC) was associated with mitochondrial depolarization, activation of caspases, the release of cytochrome c from the mitochondria, and translocation of BAX from the cytosol to the mitochondria. cAMP inhibited GCDC-induced apoptosis, caspase 3 and caspase 9 activation, and cytochrome c release in a PI3K-dependent manner. cAMP activated PI3K in p85 immunoprecipitates and resulted in PI3K-dependent activation of the survival kinase Akt. Chemical inhibition of Akt phosphorylation with SB-203580 partially blocked the protective effect of cAMP. cAMP resulted in wortmannin-independent phosphorylation of BAD and was associated with translocation of BAD from the mitochondria to the cytosol. 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.

phosphoinositide 3-kinase; Akt; cholestasis; BAX; adenosine 3',5'-cyclic monophosphate


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