MEF2C Alleviates Postoperative Cognitive Dysfunction by Repressing Ferroptosis

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2024-09-30 DOI:10.1111/cns.70066

Shanshan Wang, Zankai Wu, Xueshan Bu, Xuan Peng, Qin Zhou, Wenqin Song, Wenwei Gao, Wei Wang, Zhongyuan Xia

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Abstract

Background

Ferroptosis, a form of programmed cell death featured by lipid peroxidation, has been proposed as a potential etiology for postoperative cognitive dysfunction (POCD). Myocyte-specific enhancer factor 2C (MEF2C), a transcription factor expressed in various brain cell types, has been implicated in cognitive disorders. This study sought to ascertain whether MEF2C governs postoperative cognitive capacity by affecting ferroptosis.

Methods

Transcriptomic analysis of public data was used to identify MEF2C as a candidate differentially expressed gene in the hippocampus of POCD mice. The POCD mouse model was established via aseptic laparotomy under isoflurane anesthesia after treatment with recombinant adeno-associated virus 9 (AAV9)-mediated overexpression of MEF2C and/or the glutathione peroxidase 4 (GPX4) inhibitor RSL3. Cognitive performance, Nissl staining, and ferroptosis-related parameters were assessed. Dual-luciferase reporter gene assays and chromatin immunoprecipitation assays were implemented to elucidate the mechanism by which MEF2C transcriptionally activates GPX4.

Results

MEF2C mRNA and protein levels decreased in the mouse hippocampus following anesthesia and surgery. MEF2C overexpression ameliorated postoperative memory decline, hindered lipid peroxidation and iron accumulation, and enhanced antioxidant capacity, which were reversed by RSL3. Additionally, MEF2C was found to directly bind to the Gpx4 promoter and activate its transcription.

Conclusions

Our findings suggest that MEF2C may be a promising therapeutic target for POCD through its negative modulation of ferroptosis.

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MEF2C 通过抑制铁突变缓解术后认知功能障碍

背景：脂质过氧化是细胞程序性死亡的一种形式，已被认为是术后认知功能障碍（POCD）的潜在病因。肌细胞特异性增强因子 2C（MEF2C）是一种在多种脑细胞类型中表达的转录因子，已被认为与认知障碍有关。本研究试图确定MEF2C是否通过影响铁蛋白沉积来调节术后认知能力：方法：通过对公开数据进行转录组分析，确定MEF2C是POCD小鼠海马中差异表达的候选基因。POCD小鼠模型是在异氟醚麻醉下通过无菌开腹手术建立的，用重组腺相关病毒9（AAV9）介导的MEF2C和/或谷胱甘肽过氧化物酶4（GPX4）抑制剂RSL3进行过表达。对认知能力、Nissl染色和铁蛋白沉积相关参数进行了评估。采用双荧光素酶报告基因测定和染色质免疫沉淀测定来阐明MEF2C转录激活GPX4的机制：结果：麻醉和手术后，小鼠海马中MEF2C mRNA和蛋白水平下降。MEF2C的过表达可改善术后记忆力下降，阻碍脂质过氧化和铁积累，并增强抗氧化能力，而RSL3可逆转这些现象。此外，研究还发现MEF2C可直接与Gpx4启动子结合并激活其转录：我们的研究结果表明，MEF2C可通过其对铁跃迁的负向调节作用成为治疗POCD的一个有前景的靶点。

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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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.