CHOP plays a pivotal role in the astrocyte death induced by oxygen and glucose deprivation
CHOP plays a pivotal role in the astrocyte death induced by oxygen and glucose deprivation
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作者：
Benavides, A;Pastor, D;Calvo, S
缺血对星形胶质细胞和神经元的存活具有不同的后果。因此，星形胶质细胞显示出对众所周知会导致神经元死亡的短期缺血的显著抵抗力。我们已经使用了中风，氧和葡萄糖剥夺（OGD）的细胞培养模型，以澄清的机制负责的星形胶质细胞对缺血的排他性抵抗。通过RNA差异显示技术分析了缺血诱导的星形胶质细胞死亡和缺血后存活相关基因的表达。我们的研究表明，CEBP同源蛋白（CHOP）编码基因的表达迅速强烈上调星形胶质细胞缺氧缺糖。CHOP mRNA诱导伴随着其他基因（grp 78，grp 95）的激活，这些基因与CHOP一样参与内质网（ER）应激反应。此外，导致ER钙耗竭或蛋白N-糖基化抑制的药物模拟了OGD对星形胶质细胞存活的影响，进一步支持ER参与星形胶质细胞对OGD的反应。我们的实验还表明，在ER应激反应过程中，CHOP的上调是缺血导致星形胶质细胞死亡所必需的。不仅CHOP mRNA和蛋白水平与OGD触发的细胞损伤程度完全相关，而且CHOP反义寡核苷酸处理显著克服了OGD诱导的星形胶质细胞死亡。然而，我们观察到，星形胶质细胞发生凋亡只有当CHOP是永久上调，而不是当CHOP增加是短暂的。最后，我们发现CHOP诱导的程度取决于缺血刺激的长度。总之，我们的研究结果表明，永久上调CHOP是决定性的诱导星形胶质细胞死亡的OGD。(c)2005 Wiley-Liss，Inc.
Ischemia has different consequences on the survival of astrocytes and neurons. Thus, astrocytes show a remarkable resistance to short periods of ischemia that are well known to cause neuronal death. We have used a cell culture model of stroke, oxygen, and glucose deprivation (OGD), to clarify the mechanisms responsible for the exclusive resistance of astrocytes to ischemia. The expression of genes implicated in both ischemia-induced astrocyte death and post-ischemic survival was analysed by the RNA differential display technique. Our study revealed that the expression of the CEBP homologous protein (CHOP)-coding gene is promptly an intensely upregulated following astrocyte oxygen and glucose deprivation. CHOP mRNA induction was accompanied by the activation of other genes (grp78, grp95) that, alike CHOP, are involved in the endoplasmic reticulum (ER) stress response. In addition, drugs that cause ER calcium depletion or protein N-glycosylation inhibition mimicked the effects of OGD on astrocyte survival, further supporting the involvement of ER in the astrocyte responses to OGD. Our experiments also demonstrated that upregulation of CHOP during the ER stress response is required for ischemia to cause astrocyte death. Not only the levels of CHOP mRNA and protein correlate perfectly with the degree of OGD-triggered cell injury, but also astrocyte death induced by OGD is significantly overcome by CHOP antisense oligonucleotide treatment. Nevertheless, we observed that astrocytes undergo apoptosis only when CHOP is permanently upregulated, and not when CHOP increases are transient. Finally, we found that the extent of CHOP induction is determined by the length of the ischemic stimulus. Taken together, our results indicate that permanent upregulation of CHOP is decisive for the induction of astrocyte death by OGD. (c) 2005 Wiley-Liss, Inc.