Preventing hypoxia/reoxygenation damage to hepatocytes by p66(shc) ablation: up-regulation of anti-oxidant and anti-apoptotic proteins.

@article{citeulike:3340356, abstract = {BACKGROUND/AIMS: Ischemia/reperfusion damage to the liver remains a serious concern in many clinical situations. Major mechanisms for this certainly include oxidative stress. METHODS: The effects of ablating the p66 isoform of ShcA (p66(shc)) on hypoxia/reoxygenation (H/R)-induced oxidative stress and cell injury in hepatocytes were investigated. RESULTS: Immediately after reoxygenation, AML12 cells were clearly under oxidative stress; many cells underwent apoptosis. However, knockdown of p66(shc) by specific RNAi markedly decreased cellular oxidative stress and H/R-induced apoptosis, as well as conferring resistance to H(2)O(2) insult. These data suggest that prevention of apoptosis conferred by ablation of p66(shc) results from changed ROS-scavenging, but not inhibition of ROS generation. These data were also confirmed in fibroblasts from p66(shc) knockout mice. Anti-oxidant molecules, such as MnSOD and Ref-1 and the anti-apoptotic molecule Bcl-xL were up-regulated, and pro-apoptotic FLICE was down-regulated, by ablation of p66(shc). Interestingly, catalase expression was not affected in p66(shc)-knockdown-AML12 cells although it is a major target in other cell types. CONCLUSIONS: Our findings suggest that in hepatocytes, ablation of p66(shc) is cytoprotective against H/R-induced oxidative stress, with MnSOD and Ref-1 playing critical roles, and with up-regulation of Bcl-xL and down-regulation of FLICE contributing jointly to preventing cells from undergoing oxidant-induced apoptosis.}, address = {Department of Surgery, Hokkaido University School of Medicine, Sapporo, Hokkaido, Japan.}, author = {Haga, S. and Terui, K. and Fukai, M. and Oikawa, Y. and Irani, K. and Furukawa, H. and Todo, S. and Ozaki, M. }, citeulike-article-id = {3340356}, doi = {http://dx.doi.org/10.1016/j.jhep.2007.11.018}, issn = {0168-8278}, journal = {Journal of hepatology}, keywords = {apoptosis, hepatocyte, hypoxia, knockout, ros, shc}, month = {March}, number = {3}, pages = {422--432}, posted-at = {2008-09-26 16:52:52}, priority = {2}, title = {Preventing hypoxia/reoxygenation damage to hepatocytes by p66(shc) ablation: up-regulation of anti-oxidant and anti-apoptotic proteins.}, url = {http://dx.doi.org/10.1016/j.jhep.2007.11.018}, volume = {48}, year = {2008} }

TY - JOUR ID - citeulike:3340356 L3 - citeulike-article-id:3340356 N2 - BACKGROUND/AIMS: Ischemia/reperfusion damage to the liver remains a serious concern in many clinical situations. Major mechanisms for this certainly include oxidative stress. METHODS: The effects of ablating the p66 isoform of ShcA (p66(shc)) on hypoxia/reoxygenation (H/R)-induced oxidative stress and cell injury in hepatocytes were investigated. RESULTS: Immediately after reoxygenation, AML12 cells were clearly under oxidative stress; many cells underwent apoptosis. However, knockdown of p66(shc) by specific RNAi markedly decreased cellular oxidative stress and H/R-induced apoptosis, as well as conferring resistance to H(2)O(2) insult. These data suggest that prevention of apoptosis conferred by ablation of p66(shc) results from changed ROS-scavenging, but not inhibition of ROS generation. These data were also confirmed in fibroblasts from p66(shc) knockout mice. Anti-oxidant molecules, such as MnSOD and Ref-1 and the anti-apoptotic molecule Bcl-xL were up-regulated, and pro-apoptotic FLICE was down-regulated, by ablation of p66(shc). Interestingly, catalase expression was not affected in p66(shc)-knockdown-AML12 cells although it is a major target in other cell types. CONCLUSIONS: Our findings suggest that in hepatocytes, ablation of p66(shc) is cytoprotective against H/R-induced oxidative stress, with MnSOD and Ref-1 playing critical roles, and with up-regulation of Bcl-xL and down-regulation of FLICE contributing jointly to preventing cells from undergoing oxidant-induced apoptosis. IS - 3 JF - Journal of hepatology SN - 0168-8278 AD - Department of Surgery, Hokkaido University School of Medicine, Sapporo, Hokkaido, Japan. EP - 432 TI - Preventing hypoxia/reoxygenation damage to hepatocytes by p66(shc) ablation: up-regulation of anti-oxidant and anti-apoptotic proteins. VL - 48 SP - 422 KW - apoptosis KW - hepatocyte KW - hypoxia KW - knockout KW - ros KW - shc AU - Haga, S AU - Terui, K AU - Fukai, M AU - Oikawa, Y AU - Irani, K AU - Furukawa, H AU - Todo, S AU - Ozaki, M PY - 2008/03// UR - http://dx.doi.org/10.1016/j.jhep.2007.11.018 ER -