Targeting miR‐124/Ferroportin signaling ameliorated neuronal cell death through inhibiting apoptosis and ferroptosis in aged intracerebral hemorrhage murine model,Aging Cell

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Targeting miR‐124/Ferroportin signaling ameliorated neuronal cell death through inhibiting apoptosis and ferroptosis in aged intracerebral hemorrhage murine model
Aging Cell ( IF 8.0 ) Pub Date : 2020-10-17 , DOI: 10.1111/acel.13235
Wen-Dai Bao _{1,

2} , Xiao-Ting Zhou _{1,

2} , Lan-Ting Zhou _{1,

2} , Fudi Wang ₃ , Xiaoping Yin _{4,

5} , Youming Lu ₂ , Ling-Qiang Zhu _{1,

2} , Dan Liu ₂

Affiliation

Incidence of intracerebral hemorrhage (ICH) and brain iron accumulation increases with age. Excess iron accumulation in brain tissues post‐ICH induces oxidative stress and neuronal damage. However, the mechanisms underlying iron deregulation in ICH, especially in the aged ICH model have not been well elucidated. Ferroportin1 (Fpn) is the only identified nonheme iron exporter in mammals to date. In our study, we reported that Fpn was significantly upregulated in perihematomal brain tissues of both aged ICH patients and mouse model. Fpn deficiency induced by injecting an adeno‐associated virus (AAV) overexpressing cre recombinase into aged Fpn‐floxed mice significantly worsened the symptoms post‐ICH, including hematoma volume, cell apoptosis, iron accumulation, and neurologic dysfunction. Meanwhile, aged mice pretreated with a virus overexpressing Fpn showed significant improvement of these symptoms. Additionally, based on prediction of website tools, expression level of potential miRNAs in ICH tissues and results of luciferase reporter assays, miR‐124 was identified to regulate Fpn expression post‐ICH. Higher serum miR‐124 levels were correlated with poor neurologic scores of aged ICH patients. Administration of miR‐124 antagomir enhanced Fpn expression and attenuated iron accumulation in aged mice model. Both apoptosis and ferroptosis, but not necroptosis, were regulated by miR‐124/Fpn signaling manipulation. Our study demonstrated the critical role of miR‐124/Fpn signaling in iron metabolism and neuronal death post‐ICH in aged murine model. Thus, Fpn upregulation or miR‐124 inhibition might be promising therapeutic approachs for this disease.

中文翻译：

靶向 miR-124/Ferroportin 信号通过抑制老年脑出血小鼠模型的细胞凋亡和铁死亡改善神经元细胞死亡

脑出血 (ICH) 和脑铁积累的发生率随着年龄的增长而增加。ICH 后脑组织中过量的铁积累会诱导氧化应激和神经元损伤。然而，ICH 中铁失调的机制尚未得到很好的阐明，尤其是在老年 ICH 模型中。Ferroportin1 (Fpn) 是迄今为止哺乳动物中唯一确定的非血红素铁输出体。在我们的研究中，我们报道了老年 ICH 患者和小鼠模型的血肿周围脑组织中 Fpn 显着上调。通过将过表达 cre 重组酶的腺相关病毒 (AAV) 注射到老年 Fpn floxed 小鼠体内，导致 Fpn 缺乏显着恶化 ICH 后的症状，包括血肿体积、细胞凋亡、铁积累和神经功能障碍。同时，用过表达 Fpn 的病毒预处理的老年小鼠显示出这些症状的显着改善。此外，根据网站工具的预测、ICH 组织中潜在 miRNA 的表达水平和荧光素酶报告基因检测的结果，确定了 miR-124 可调节 ICH 后 Fpn 的表达。较高的血清 miR-124 水平与老年 ICH 患者较差的神经系统评分相关。miR-124 antagomir 的给药增强了老年小鼠模型中 Fpn 的表达并减弱了铁的积累。细胞凋亡和铁死亡，但不是坏死性凋亡，均受 miR-124/Fpn 信号操纵调节。我们的研究证明了 miR-124/Fpn 信号在老年小鼠模型中 ICH 后铁代谢和神经元死亡中的关键作用。因此，

更新日期：2020-11-23

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