Enriched Environment Attenuates Ferroptosis after Cerebral Ischemia/Reperfusion Injury via the HIF-1α-ACSL4 Pathway.
Enriched Environment Attenuates Ferroptosis after Cerebral Ischemia/Reperfusion Injury via the HIF-1α-ACSL4 Pathway.
复制标题
丰富的环境通过 HIF-1α-ACSL4 途径减轻脑缺血/再灌注损伤后的铁死亡
DOI：
10.1155/2023/5157417
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发表时间：
2023
影响因子：
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通讯作者：
Zhang, Xin
中科院分区：
文献类型：
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作者：
Liu, Jingying;Luo, Qihang;Ke, Jie;Zhang, DongDong;Xu, Yang;Liao, Weijing;Chen, Xiuping;Zhang, Xin
丰富环境（EE）已被证明是一种有效的干预策略，可以改善脑缺血/再灌注（I/R）损伤后的神经功能恢复。然而，其背后的机制仍需要进一步研究。最近，研究表明铁死亡在缺血性中风（IS）的病理生理发展中发挥着重要作用。本研究旨在探讨 EE 是否通过减轻脑 I/R 损伤后的铁死亡来发挥神经保护作用。我们采用大脑中动脉闭塞/再灌注（MCAO/R）建立脑缺血再灌注损伤模型。为了评估 EE 对神经功能恢复的影响，我们使用了改良的神经功能严重程度评分 (mNSS) 和莫里斯水迷宫 (MWM)。我们使用蛋白质印迹法检测谷胱甘肽过氧化物酶4（GPX4）、缺氧诱导因子1α（HIF-1α）和酰基辅酶A合成酶长链家族成员4（ACSL4）的蛋白水平。我们使用实时定量 PCR (qRT-PCR) 来测量 ACSL4 和炎症细胞因子的 mRNA 水平，包括肿瘤坏死因子 α (TNFα)、白细胞介素 6 (IL-6) 和白细胞介素 1 β (IL-1β)。通过 TdT 介导的 dUTP 缺口末端标记 (TUNEL) 测定、二氨基联苯胺 (DAB-) 增强 Perls 染色、铁水平测定和丙二醛 (MDA) 水平测定来检测铁死亡的发生。结果证实，EE 可促进脑缺血再灌注损伤后的功能恢复并减轻铁死亡和神经炎症。 EE增加HIF-1α的表达，同时抑制ACSL4的表达。我们的研究表明，EE通过减轻铁死亡来改善脑缺血再灌注损伤后的功能恢复，这可能与其调节神经炎症和HIF-1α-ACSL4通路有关。
Enriched environment (EE) has been proven to be an effective intervention strategy which can improve neurofunctional recovery following cerebral ischemia/reperfusion (I/R) injury. However, it still needs further investigation for the underlying mechanisms. Recently, it has been shown that ferroptosis played an essential role in the pathophysiological development of ischemic stroke (IS). This study is aimed at investigating whether EE plays a neuroprotective role by attenuating ferroptosis after cerebral I/R injury. We used middle cerebral artery occlusion/reperfusion (MCAO/R) to build a model of cerebral I/R injury. To evaluate the effect of EE on neurological recovery, we used the modified neurological severity score (mNSS) and the Morris water maze (MWM). We used the western blot to detect the protein levels of glutathione peroxidase 4 (GPX4), hypoxia-inducible factor-1α (HIF-1α), and acyl-CoA synthetase long-chain family member 4 (ACSL4). We used the quantitative real-time PCR (qRT-PCR) to measure the mRNA levels of ACSL4 and inflammatory cytokines including tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and interleukin 1 beta (IL-1β). The occurrence of ferroptosis was detected by TdT-mediated dUTP nick-end labeling (TUNEL) assay, diaminobenzidine- (DAB-) enhanced Perls' staining, iron level assays, and malondialdehyde (MDA) level assays. The results verified that EE enhanced functional recovery and attenuated ferroptosis and neuroinflammation after cerebral I/R injury. EE increased the expression of HIF-1α while inhibited the expression of ACSL4. Our research indicated that EE improved functional recovery after cerebral I/R injury through attenuating ferroptosis, and this might be related to its regulation of the neuroinflammation and HIF-1α-ACSL4 pathway.