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GRP94 (94 kDa glucose-regulated protein) suppresses ischemic neuronal cell death against ischemia/reperfusion injury

Authors

  • Yoshio Bando,

    1. Department of Anatomy and Neuroscience, Osaka University Graduate School of Medicine, Osaka, Japan
    2. Core Research for Evolutional Science and Technology, Japan Science and Technology (CREST JST), Saitama Japan
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  • Taiichi Katayama,

    1. Department of Anatomy and Neuroscience, Osaka University Graduate School of Medicine, Osaka, Japan
    2. Core Research for Evolutional Science and Technology, Japan Science and Technology (CREST JST), Saitama Japan
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  • Kousuke Kasai,

    1. Department of Traumatology, Osaka University Graduate School of Medicine, Osaka, Japan
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  • Manabu Taniguchi,

    1. Department of Anatomy and Neuroscience, Osaka University Graduate School of Medicine, Osaka, Japan
    2. Core Research for Evolutional Science and Technology, Japan Science and Technology (CREST JST), Saitama Japan
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  • Michio Tamatani,

    1. Department of Anatomy and Neuroscience, Osaka University Graduate School of Medicine, Osaka, Japan
    2. Core Research for Evolutional Science and Technology, Japan Science and Technology (CREST JST), Saitama Japan
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  • Masaya Tohyama

    1. Department of Anatomy and Neuroscience, Osaka University Graduate School of Medicine, Osaka, Japan
    2. Core Research for Evolutional Science and Technology, Japan Science and Technology (CREST JST), Saitama Japan
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  • *

    Present address: Department of Anatomy, Asahikawa Medical College, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido 078–8510, Japan.

: Dr Yoshio Bando, *present address below.
E-mail: ybando@asahikawa-med.ac.jp

Abstract

The 94 kDa glucose-regulated protein (GRP94), the endoplasmic reticulum (ER) resident molecular chaperone, has a role in cell death due to endoplasmic reticulum stress (ER stress). Here, we report that expression of GRP94 was increased in human neuroblastoma cells (SH-SY5Y (SY5Y) cells) exposed to hypoxia/reoxygenation (H/R). H/R mediated death of SY5Y cells was associated with the activation of major cysteine proteases, caspase-3 and calpain, along with an elevated intracellular calcium concentration. Pretreatment with adenovirus-mediated antisense GRP94 (AdGRP94AS) led to reduced viability of SY5Y cells after being subjected to H/R compared with wild-type cells or cells with adenovirus-mediated overexpression of GRP94 (AdGRP94S). These results indicate that suppression of GRP94 is associated with accelerated apoptosis and that expression of GRP94 (as a stress protein) suppresses oxidative stress-mediated neuronal death and stabilizes calcium homeostasis in the ER. We also used gerbils with transient forebrain ischemia to study the role of GRP94 in vivo. Neurons with adenovirus-mediated overexpression of GRP94 were resistant to ischemic damage. These results confirmed that GRP94 could suppress ischemic injury to neurons, suggesting that gene transfer of GRP94 into the brain may have therapeutic potential in the treatment of cerebrovascular disease.

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