title: GRP94 (94 kDa glucose-regulated protein) suppresses ischemic neuronal cell death against ischemia/reperfusion injury.
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.
authors.affiliation: Department of Anatomy and Neuroscience, Osaka University Graduate School of Medicine, Osaka, Japan. ybando@asahikawa-med.ac.jp
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Bando
authors.forename: Taiichi
authors.initials: T
authors.lastname: Katayama
authors.forename: Kousuke
authors.initials: K
authors.lastname: Kasai
authors.forename: Manabu
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Michio
authors.initials: M
authors.lastname: Tamatani
authors.forename: Masaya
authors.initials: M
authors.lastname: Tohyama
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D002561:Cerebrovascular Disorders / Q000378:metabolism / Q000503:physiopathology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004274:DNA, Recombinant; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005849:Gerbillinae; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D023421:Models, Animal; D009447:Neuroblastoma; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D015427:Reperfusion Injury; D014407:Tumor Cells, Cultured
chemical_list: D004274:DNA, Recombinant; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; C018551:glucose-regulated proteins; C505407:CASP3 protein, human; D002154:Calpain; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D002118:Calcium