GRP94 (94 kDa glucose-regulated protein) suppresses ischemic neuronal cell death against ischemia/reperfusion injury
GRP94 (94 kDa glucose-regulated protein) suppresses ischemic neuronal cell death against ischemia/reperfusion injury
复制标题
DOI：
10.1046/j.1460-9568.2003.02818.x
复制
发表时间：
2003-08-01
影响因子：
3.4
通讯作者：
Tohyama, M
中科院分区：
文献类型：
--
作者：
Bando, Y;Katayama, T;Tohyama, M
94 kDa 葡萄糖调节蛋白 (GRP94) 是内质网 (ER) 常驻分子伴侣，在内质网应激（ER 应激）引起的细胞死亡中发挥作用。在这里，我们报告在暴露于缺氧/复氧（H/R）的人神经母细胞瘤细胞（SH-SY5Y（SY5Y）细胞）中GRP94的表达增加。 H/R 介导的 SY5Y 细胞死亡与主要半胱氨酸蛋白酶、Caspase-3 和钙蛋白酶的激活以及细胞内钙浓度升高有关。与野生型细胞或腺病毒介导的 GRP94 过表达 (AdGRP94S) 的细胞相比，腺病毒介导的反义 GRP94 (AdGRP94AS) 预处理导致 SY5Y 细胞在进行 H/R 后活力降低。这些结果表明，GRP94 的抑制与细胞凋亡加速相关，并且 GRP94（作为应激蛋白）的表达抑制氧化应激介导的神经元死亡并稳定 ER 中的钙稳态。我们还使用具有短暂前脑缺血的沙鼠来研究 GRP94 在体内的作用。腺病毒介导的 GRP94 过度表达的神经元对缺血性损伤具有抵抗力。这些结果证实GRP94可以抑制神经元的缺血性损伤，这表明将GRP94基因转移到大脑中可能具有治疗脑血管疾病的潜力。
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.