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.