Down-regulation of GRP78 enhances apoptosis via CHOP pathway in retinal ischemia-reperfusion injury
Down-regulation of GRP78 enhances apoptosis via CHOP pathway in retinal ischemia-reperfusion injury
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DOI：
10.1016/j.neulet.2014.05.042
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发表时间：
2014-07-11
影响因子：
2.5
通讯作者：
Tang, Luosheng
中科院分区：
文献类型：
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作者：
Li, Huiling;Zhu, Xiaohua;Tang, Luosheng
缺血再灌注(I/R)损伤是视网膜细胞凋亡的主要原因。但机制仍然难以捉摸。在I/R损伤过程中，细胞内钙离子水平升高，导致产生活性氧，从而导致内质网(ER)应激。然而，细胞凋亡与内质网应激在视网膜I/R损伤中的相关性却知之甚少。在本研究中，我们证明了内质网应激在大鼠视网膜I/R模型中被激活。I/R视网膜内质网应激相关分子、葡萄糖调节蛋白78(GRP78)和C/EBP同源蛋白(CHOP)的转录表达显著增加，并呈时间依赖性。反义寡核苷酸部分抑制GRP78内源性表达可导致大鼠视网膜损伤和细胞凋亡。此外，CHOP的转录表达持续增加。我们的研究结果表明，内质网应激可能在I/R损伤所致的视网膜损伤中起关键作用，GRP78可能在I/R视网膜发挥抗细胞凋亡作用。重要的是，CHOP的持续高表达可能是GRP78下调后增强I/R诱导的细胞凋亡的可能机制之一。这些结果可能为深入了解视网膜I/R损伤的病理机制提供依据。(C)2014爱思唯尔爱尔兰有限公司。保留所有权利。
Ischemia/reperfusion (I/R) injury is the main cause of retinal apoptosis. But the mechanism remains elusive. During I/R injury, the intracellular calcium levels increase, resulting in the generation of reactive oxygen species, which have been shown to cause endoplasmic reticulum (ER) stress. However, little is known about the correlation between apoptosis and ER stress in retinal I/R injury. In the present study, we demonstrated that ER stress was activated in the retina of rat I/R models. The transcriptional expression of ER stress-associated molecules, glucose-regulated protein-78 (GRP78) and C/EBP-homologous protein (CHOP) were significantly increased in I/R retinas in a time-dependent manner. Partial inhibition of the endogenous expression of GRP78 with antisense oligonucleotide resulted in significant retinal damage and apoptosis in I/R injury rats. Also, the transcriptional expression of CHOP was persistently increased. Our findings indicate that ER stress may play a critical role in I/R injury induced retinal damage, and GRP78 may exert anti-apoptotic actions in I/R retina. Importantly, the persistent high expression of CHOP might serve as a possible mechanism that contributes to the enhanced the I/R-induced apoptosis after GRP78 down-regulation. These results may provide insight into the pathology of retinal I/R injury. (C) 2014 Elsevier Ireland Ltd. All rights reserved.