Apelin-13 Alleviates Early Brain Injury after Subarachnoid Hemorrhage via Suppression of Endoplasmic Reticulum Stress-mediated Apoptosis and Blood-Brain Barrier Disruption: Possible Involvement of ATF6/CHOP Pathway
Apelin-13 Alleviates Early Brain Injury after Subarachnoid Hemorrhage via Suppression of Endoplasmic Reticulum Stress-mediated Apoptosis and Blood-Brain Barrier Disruption: Possible Involvement of ATF6/CHOP Pathway
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Apelin-13 通过抑制内质网应激介导的细胞凋亡和血脑屏障破坏来减轻蛛网膜下腔出血后的早期脑损伤：可能涉及 ATF6/CHOP 通路
DOI：
10.1016/j.neuroscience.2018.07.023
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发表时间：
2018-09-15
期刊：
影响因子：
3.3
通讯作者：
Zhang, Jianmin
中科院分区：
文献类型：
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作者：
Xu, Weilin;Gao, Liansheng;Zhang, Jianmin
神经细胞凋亡在蛛网膜下腔出血（SAH）后早期脑损伤中起重要作用。这项研究首次表明，apelin-13抑制转录激活因子6（ATF 6）可以减少SAH后内质网（ER）应激介导的细胞凋亡和血脑屏障（BBB）破坏。我们选择了apelin-13、ATF 6和CCAAT/增强子结合蛋白（C/EBP）同源蛋白（CHOP）siRNA来验证这一假设。SAH后24 h进行脑含水量、神经行为学和伊文思蓝（EB）测定。Western blot分析和逆转录-聚合酶链反应（RT-PCR），以评估在蛋白质和mRNA水平的目标的表达。用末端脱氧核苷酸转移酶（TdT）介导的dUTP缺口末端标记法（TUNEL）和caspase-3染色检测神经元凋亡。结果表明，SAH后ATF 6及其下游蛋白CHOP表达上调，24 h达高峰。ATF 6在神经元中高表达。给予apelin-13可显著降低ATF 6及其下游靶标CHOP和caspase-3的mRNA和蛋白水平，但增加Bcl-2/Bax比率、Claudin-5、Occludin和ZO-1。应用apelin-13可减轻脑水肿，改善血脑屏障破坏，改善神经功能。然而，CHOP siRNA可以显著逆转SAH后ATF 6水平升高诱导的促凋亡作用。Apelin-13可能通过抑制ER应激反应通路中的ATF 6/CHOP臂发挥其对SAH后早期脑损伤的神经保护作用。(C)2018年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Neuronal apoptosis plays important roles in the early brain injury after subarachnoid hemorrhage (SAH). This study first showed that inhibition of activating transcription factor 6 (ATF6) by apelin-13 could reduce endoplasmic reticulum (ER)-stress-mediated apoptosis and blood-brain-barrier (BBB) disruption after SAH. We chose apelin-13, ATF6 and CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) siRNAs to verify the hypothesis. Brain water content, neurological behavior and Evans Blue (EB) were assessed at 24 h after SAH. Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) were applied to evaluate the expression of targets in both protein and mRNA levels. Neuronal apoptosis was assessed with Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) and caspase-3 staining. The results showed that the levels of ATF6, and its downstream protein, CHOP were upregulated and reached the peak at 24 h after SAH. ATF6 was highly expressed in neurons. The administration of apelin-13 could significantly reduce the mRNA and protein levels of ATF6, and its downstream targets, CHOP and caspase-3, but increase the Bcl-2/Bax ratio, Claudin-5, Occludin and ZO-1. What's more, the administration of apelin-13 could reduce brain edema, ameliorate BBB disruption and improve neurological functions. However, the CHOP siRNA could significantly reverse the pro-apoptotic effect induced by the increased ATF6 level after SAH. Apelin-13 could exert its neuroprotective effects via suppression of ATF6/CHOP arm of ER-stress-response pathway in the early brain injury after SAH. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.