脂褐素-2通过调节HMGB1/Nrf2/HO-1通路促进内皮细胞铁凋亡,从而加重静脉溶栓后的血脑屏障功能障碍

IF 10.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Redox Biology Pub Date : 2024-09-05 DOI:10.1016/j.redox.2024.103342
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引用次数: 0

摘要

背景血脑屏障(BBB)破坏是急性缺血性卒中(AIS)患者静脉溶栓(IVT)后出血转化(HT)的主要原因。方法 100 例接受静脉溶栓的 AIS 患者(42 例在静脉溶栓 24 小时后发生出血性转化,58 例未发生出血性转化)被纳入研究。在细胞因子芯片的基础上,检测了入院时血清中几种 AIS 相关蛋白的水平,包括 LCN2、铁蛋白、基质金属蛋白酶-3、血管内皮源性生长因子和 X 连锁细胞凋亡抑制因子,并分析了它们与 HT 的关系。结果在 IVT 后的 AIS 患者中,逻辑回归分析显示基线血清 LCN2(p = 0.023)和铁蛋白(p = 0.046)水平与 HT 独立相关。HT 患者的血清 LCN2 和铁蛋白水平呈正相关。在实验研究中,重组 LCN2(rLCN2)可明显加重血栓栓塞性卒中大鼠溶栓后的 BBB 功能障碍和 HT,而 ZINC006440089 对 LCN2 的抑制作用则相反。进一步的机理研究表明,LCN2 促进了内皮细胞的铁变态反应,同时还诱导了高迁移率基团框 1(HMGB1),抑制了核因子 E2 相关因子 2(Nrf2)和血红素加氧酶 1(HO-1)蛋白的核转位。铁氧化抑制剂铁前列素-1(fer-1)能显著限制 LCN2 介导的 BBB 破坏。结论LCN2通过调节HMGB1/Nrf2/HO-1通路促进内皮细胞铁突变,从而加剧了溶栓后BBB的破坏,这可能为预防IVT后高血压提供了一个有前景的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Lipocalin-2 aggravates blood-brain barrier dysfunction after intravenous thrombolysis by promoting endothelial cell ferroptosis via regulating the HMGB1/Nrf2/HO-1 pathway

Background

Disruption of the blood-brain barrier (BBB) is a major contributor to hemorrhagic transformation (HT) in patients with acute ischemic stroke (AIS) following intravenous thrombolysis (IVT). However, the clinical therapies aimed at BBB protection after IVT remain limited.

Methods

One hundred patients with AIS who underwent IVT were enrolled (42 with HT and 58 without HT 24 h after IVT). Based on the cytokine chip, the serum levels of several AIS-related proteins, including LCN2, ferritin, matrix metalloproteinase-3, vascular endothelial-derived growth factor, and X-linked inhibitor of apoptosis, were detected upon admission, and their associations with HT were analyzed. After finding that LCN2 was related to HT in patients with IVT, we clarified whether the modulation of LCN2 influenced BBB dysfunction and HT after thrombolysis and investigated the potential mechanism.

Results

In patients with AIS following IVT, logistic regression analysis showed that baseline serum LCN2 (p = 0.023) and ferritin (p = 0.046) levels were independently associated with HT. A positive correlation between serum LCN2 and ferritin levels was identified in patients with HT. In experimental studies, recombinant LCN2 (rLCN2) significantly aggravated BBB dysfunction and HT in the thromboembolic stroke rats after thrombolysis, whereas LCN2 inhibition by ZINC006440089 exerted opposite effects. Further mechanistic studies showed that, LCN2 promoted endothelial cell ferroptosis, accompanied by the induction of high mobility group box 1 (HMGB1) and the inhibition of nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins. Ferroptosis inhibitor ferrostatin-1 (fer-1) significantly restricted the LCN2-mediated BBB disruption. Transfection of LCN2 and HMGB1 siRNA inhibited the endothelial cell ferroptosis, and this effects was reversed by Nrf2 siRNA.

Conclusion

LCN2 aggravated BBB disruption after thrombolysis by promoting endothelial cell ferroptosis via regulating the HMGB1/Nrf2/HO-1 pathway, this may provide a promising therapeutic target for the prevention of HT after IVT.

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来源期刊
Redox Biology
Redox Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
19.90
自引率
3.50%
发文量
318
审稿时长
25 days
期刊介绍: Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease. Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.
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