纳多洛尔通过靶向 HOIL-1/IRP2 通路减轻缺血性脑卒中大鼠脑细胞铁素沉着

Xiao-Yan Yang, Wen-Jun Zhu, Di-Chen, Dan Peng, Jun Peng, Zhi-Jun Zhou, Xiu-Ju Luo
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引用次数: 0

摘要

导言:血红素氧化铁调控蛋白2(IRP2)泛素连接酶-1(HOIL-1)被认为有助于IRP2的泛素化,从而促进转铁蛋白受体1(TfR1)的转录,同时阻止铁蛋白-1(FPN-1)的转录。生物信息学分析预测纳多洛尔(一种β-受体阻滞剂)与 HOIL-1 相互作用:本研究旨在探讨纳多洛尔是否能通过靶向 HOIL-1/IRP2 通路抑制缺血性脑卒中大鼠脑内的铁蛋白沉积。通过阻断大脑中动脉2小时加24小时再灌注建立缺血性脑卒中大鼠模型,在再灌注后1小时给予纳多洛尔(2.5或5 mg/kg)。对 HT22 细胞进行 12 小时缺氧,然后进行 24 小时复氧以模拟缺血性脑卒中,并在复氧前在培养液中加入纳多洛尔(0.1 或 0.25 μM):结果:中风大鼠表现出明显的脑损伤(神经功能缺损评分和梗死体积增加)和铁变态反应,IRP2和TfR1上调,HOIL-1和FPN-1下调;这些现象在纳多洛尔的作用下被逆转。在培养的 HT22 细胞中,缺氧/复氧诱导的 LDH 释放、铁变态反应以及相关蛋白(IRP2、TfR1、HOIL-1 和 FPN-1)水平的变化也被纳多洛尔逆转:结论:根据上述研究结果,纳多洛尔可通过靶向 HOIL-1/IRP2 通路保护缺血大鼠大脑免受铁蛋白沉积的影响,从而防止细胞内铁超载。因此,纳多洛尔可能是治疗缺血性中风患者的新适应症。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Nadolol Attenuates Brain Cell Ferroptosis in Ischemic Stroke Rats by Targeting the HOIL-1/IRP2 Pathway.

Introduction: Heme-oxidized iron regulatory protein 2 (IRP2) ubiquitin ligase-1 (HOIL-1) is believed to contribute to the ubiquitination of IRP2, which facilitates the transcription of transferrin receptor 1 (TfR1) while preventing the transcription of ferroportin-1 (FPN-1). Bioinformatics analysis predicts that nadolol (a β-blocker) interacts with the HOIL-1.

Method: The present study is intended to explore whether nadolol suppresses ferroptosis in the brains of rats suffering from ischemic stroke via targeting the HOIL-1/IRP2 pathway. A rat model of ischemic stroke was established by blocking the middle cerebral artery for 2 h plus 24 h reperfusion, and nadolol (2.5 or 5 mg/kg) was given at 1h after reperfusion. HT22 cells were subjected to 12 h of hypoxia, followed by 24 h of reoxygenation for simulating ischemic stroke, and nadolol (0.1 or 0.25 μM) was administered to the culture medium before reoxygenation.

Results: The stroke rats showed evident brain injury (increases in neurological deficit score and infarct volume) and ferroptosis, along with up-regulation of IRP2 and TfR1 while downregulation of HOIL-1 and FPN-1; these phenomena were reversed in the presence of nadolol. In the cultured HT22 cells, hypoxia/reoxygenation-induced LDH release, ferroptosis, and changes in the levels of relevant proteins (IRP2, TfR1, HOIL-1, and FPN-1) were also reversed by nadolol.

Conclusion: In terms of these findings, it is concluded that nadolol can protect the ischemic rats' brains against ferroptosis by targeting the HOIL-1/IRP2 pathway, thereby preventing intracellular iron overload. Thus, nadolol may be a novel indication for treating patients with ischemic stroke.

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