Protective effects of brain and muscle ARNT-like gene 1 on oxidized low-density lipoprotein-induced human brain microvascular endothelial cell injury by alleviating ferroptosis.

IF 2.7 4区医学 Q3 TOXICOLOGY

Human & Experimental Toxicology Pub Date : 2023-01-01 DOI:10.1177/09603271231184630

Shui Yu, Yijun Zeng, Chenbin Ruan, Lei Bai, Zhang Liang

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Abstract

Ferroptosis plays an important role in atherosclerotic cerebrovascular diseases. The brain and muscle ARNT-like gene 1 (BMAL1) is an important mediator in the progression of cerebrovascular diseases. However, whether BMAL1 regulates ferroptosis in atherosclerotic cerebrovascular diseases remains obscure. Here, human brain microvascular endothelial cells (HBMECs) were exposed to oxidized low-density lipoprotein (ox-LDL) to imitate cerebrovascular atherosclerosis. It was found that ox-LDL treatment induced ferroptosis events and reduced BMAL1 expression in HBMECs, which could be reversed by ferroptosis inhibitor ferrostatin-1. Furthermore, BMAL1 overexpression markedly mitigated ox-LDL-induced ferroptosis events and cell damage. Moreover, BMAL1 overexpression significantly promoted nuclear factor erythroid 2-related factor 2 (Nrf2) expression in HBMECs under ox-LDL conditions. And, Nrf2 silencing attenuated the protective effects of BMAL1 on ox-LDL-stimulated HBMEC damage and ferroptosis. Altogether, our findings delineate the cerebrovascular protective role of BMAL1/Nrf2 by antagonizing ferroptosis in response to ox-LDL stimulation and provide novel perspectives for therapeutic strategies for atherosclerotic cerebrovascular diseases.

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脑和肌肉 ARNT 样基因 1 通过减轻铁变态反应对氧化低密度脂蛋白诱导的人脑微血管内皮细胞损伤的保护作用

铁蛋白沉积症在动脉粥样硬化性脑血管疾病中发挥着重要作用。脑和肌肉 ARNT 样基因 1（BMAL1）是脑血管疾病进展过程中的一个重要介质。然而，BMAL1 是否调控动脉粥样硬化性脑血管疾病中的铁蛋白沉积仍不清楚。在此，研究人员将人脑微血管内皮细胞（HBMECs）暴露于氧化低密度脂蛋白（ox-LDL）中，以模拟脑血管动脉粥样硬化。研究发现，氧化低密度脂蛋白处理会诱导铁嗜酸事件，并降低 HBMECs 中 BMAL1 的表达，而铁嗜酸抑制剂 ferrostatin-1 可以逆转这一现象。此外，BMAL1的过表达能明显减轻氧化-LDL诱导的铁突变事件和细胞损伤。此外，在氧化-LDL条件下，BMAL1的过表达能明显促进核因子红细胞2相关因子2（Nrf2）在HBMECs中的表达。而 Nrf2 的沉默则削弱了 BMAL1 对氧化-LDL 刺激的 HBMEC 损伤和铁变态反应的保护作用。总之，我们的研究结果阐明了BMAL1/Nrf2在氧化-LDL刺激下通过拮抗铁突变对脑血管的保护作用，并为动脉粥样硬化性脑血管疾病的治疗策略提供了新的视角。

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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来源期刊

Human & Experimental Toxicology 医学-毒理学

CiteScore

5.70

自引率

3.60%

发文量

128

审稿时长

2.3 months

期刊介绍： Human and Experimental Toxicology (HET), an international peer reviewed journal, is dedicated to publishing preclinical and clinical original research papers and in-depth reviews that comprehensively cover studies of functional, biochemical and structural disorders in toxicology. The principal aim of the HET is to publish timely high impact hypothesis driven scholarly work with an international scope. The journal publishes on: Structural, functional, biochemical, and molecular effects of toxic agents; Studies that address mechanisms/modes of toxicity; Safety evaluation of novel chemical, biotechnologically-derived products, and nanomaterials for human health assessment including statistical and mechanism-based approaches; Novel methods or approaches to research on animal and human tissues (medical and veterinary patients) investigating functional, biochemical and structural disorder; in vitro techniques, particularly those supporting alternative methods