Hes1 Knockdown Exacerbates Ischemic Stroke Following tMCAO by Increasing ER Stress-Dependent Apoptosis via the PERK/eIF2α/ATF4/CHOP Signaling Pathway
Hes1 Knockdown Exacerbates Ischemic Stroke Following tMCAO by Increasing ER Stress-Dependent Apoptosis via the PERK/eIF2α/ATF4/CHOP Signaling Pathway
复制标题
DOI：
10.1007/s12264-019-00411-7
复制
发表时间：
2020-02-01
影响因子：
5.6
通讯作者：
Liao, Pinhu
中科院分区：
文献类型：
--
作者：
Li, Yueyong;Zhang, Yingjun;Liao, Pinhu
内质网应激诱导的细胞凋亡在介导缺血性卒中后脑损伤中起重要作用。最近，Hes1(Split 1的毛发和增强子)被认为参与了内质网应激的调节，但它在缺血性卒中后是否发挥作用及其机制尚不清楚。在本研究中，我们利用小鼠大脑中动脉短暂性闭塞(TMCAO)建立的缺血性卒中模型，发现脑损伤后可诱发Hes1，siRNA介导的Hes1基因敲除增加了脑梗塞的发生率，加重了神经预后，提示Hes1基因敲除可加重缺血性卒中。此外，在机制上，Hes1基因敲除促进了tMCAO后的细胞凋亡，激活了PERK/eIF2α/ATF4/CHOP信号通路。这些结果表明，Hes1基因敲除促进了内质网应激诱导的细胞凋亡。此外，用特异性抑制剂GSK2606414抑制PERK可显著减轻TMCAO后Hes1基因敲除诱导的细胞凋亡和脑梗塞的增加以及神经预后的恶化，提示Hes1对缺血性卒中的保护作用与通过调节PERK/eIF2α/ATF4/CHOP信号通路改善内质网应激有关。综上所述，这些结果揭示了Hes1基因敲除在缺血性卒中后的有害作用，并进一步将其与内质网应激诱导的细胞凋亡的调节联系起来，从而强调了靶向内质网应激在缺血性卒中治疗中的重要性。
Apoptosis induced by endoplasmic reticulum (ER) stress plays a crucial role in mediating brain damage after ischemic stroke. Recently, Hes1 (hairy and enhancer of split 1) has been implicated in the regulation of ER stress, but whether it plays a functional role after ischemic stroke and the underlying mechanism remain unclear. In this study, using a mouse model of ischemic stroke via transient middle cerebral artery occlusion (tMCAO), we found that Hes1 was induced following brain injury, and that siRNA-mediated knockdown of Hes1 increased the cerebral infarction and worsened the neurological outcome, suggesting that Hes1 knockdown exacerbates ischemic stroke. In addition, mechanistically, Hes1 knockdown promoted apoptosis and activated the PERK/eIF2 alpha/ATF4/CHOP signaling pathway after tMCAO. These results suggest that Hes1 knockdown promotes ER stress-induced apoptosis. Furthermore, inhibition of PERK with the specific inhibitor GSK2606414 markedly attenuated the Hes1 knockdown-induced apoptosis and the increased cerebral infarction as well as the worsened neurological outcome following tMCAO, implying that the protection of Hes1 against ischemic stroke is associated with the amelioration of ER stress via modulating the PERK/eIF2 alpha/ATF4/CHOP signaling pathway. Taken together, these results unveil the detrimental role of Hes1 knockdown after ischemic stroke and further relate it to the regulation of ER stress-induced apoptosis, thus highlighting the importance of targeting ER stress in the treatment of ischemic stroke.