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

Sanae Haga; Keita Terui; Moto Fukai; Yuko Oikawa; Kaikobad Irani; Hiroyuki Furukawa; Satoru Todo; Michitaka Ozaki

doi:10.1016/j.jhep.2007.11.018

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

Journal article

Peer reviewed

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

Sanae Haga, Keita Terui, Moto Fukai, Yuko Oikawa, Kaikobad Irani, Hiroyuki Furukawa, Satoru Todo and Michitaka Ozaki

Journal of hepatology, Vol.48(3), pp.422-432

03/2008

DOI: 10.1016/j.jhep.2007.11.018

PMID: 18191273

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Abstract

Ischemia/reperfusion damage to the liver remains a serious concern in many clinical situations. Major mechanisms for this certainly include oxidative stress. 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. 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. 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.

Hydrogen Peroxide - adverse effects

Cell Hypoxia - physiology

Superoxide Dismutase - genetics

Apoptosis - drug effects

Oxidative Stress - physiology

Caspase 8 - metabolism

bcl-X Protein - genetics

Apoptosis - genetics

Hepatocytes - metabolism

Caspase 8 - genetics

DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics

Up-Regulation - physiology

Reperfusion Injury - genetics

Reperfusion Injury - metabolism

Superoxide Dismutase - metabolism

Disease Models, Animal

Shc Signaling Adaptor Proteins

Cell Line

Oxidative Stress - genetics

Up-Regulation - genetics

Down-Regulation - genetics

Hydrogen Peroxide - metabolism

Mice, Knockout

Down-Regulation - physiology

Animals

Reperfusion Injury - prevention & control

Src Homology 2 Domain-Containing, Transforming Protein 1

DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism

RNA - pharmacology

Adaptor Proteins, Signal Transducing - genetics

Mice

Apoptosis - physiology

Oxidative Stress - drug effects

Adaptor Proteins, Signal Transducing - metabolism

Cell Hypoxia - genetics

bcl-X Protein - metabolism

Details

Title: Subtitle: Preventing hypoxia/reoxygenation damage to hepatocytes by p66(shc) ablation: up-regulation of anti-oxidant and anti-apoptotic proteins
Creators: Sanae Haga - Department of Surgery, Hokkaido University School of Medicine, Sapporo, Hokkaido, Japan
Keita Terui
Moto Fukai
Yuko Oikawa
Kaikobad Irani
Hiroyuki Furukawa
Satoru Todo
Michitaka Ozaki
Resource Type: Journal article
Publication Details: Journal of hepatology, Vol.48(3), pp.422-432
Publisher: Netherlands
DOI: 10.1016/j.jhep.2007.11.018
PMID: 18191273
ISSN: 0168-8278
eISSN: 1600-0641
Grant note: P01 HL 065608 / NHLBI NIH HHS
Language: English
Date published: 03/2008
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984047633102771

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