Involvement of mitochondrial- and Fas-mediated dual mechanism in CoCl2-induced apoptosis of rat PC12 cells

Hypoxic/ischemic condition induces neuronal apoptotic events, which consequently lead to neuronal cell death. However, its specific mechanistic pathways remain obscure. Cobalt chloride (CoCl2) could mimic the hypoxic condition including the production of reactive oxygen species (ROS). In this report, we investigated the signal pathway of CoCl2-induced apoptosis in PC 12 cells. The main mechanism for these apoptosis appeared to be mitochondria-mediated pathway accompanied with loss of the mitochondrial transmembrane potential (DeltaPsim) followed by cytochrome c release from the mitochondria into the cytosol, resulting in the activation of caspase-9 and caspase-3. Also, upregulation of pro-apoptotic protein Bax, and downregulation of anti-apoptotic protein Bcl-2 by presence of CoCl2 appeared significantly and it might result in activating mitochondria-mediated apoptosis. We showed that expression of Fas and Fas ligand was upregulated and caspase-8 was significantly activated in CoCl2-induced apoptotic cells. In addition, ZB4, an antagonistic Fas-antibody, inhibited the activation of caspase-8 by CoCl2, indicating that Fas receptor was involved in this pathway. These results demonstrate that CoCl2 induce apoptosis in PC 12 cells via different dual apoptosis pathway through death receptor as well as mitochondria. (C) 2004 Elsevier Ireland Ltd. All rights reserved.