Myocardial ischemia/reperfusion-induced glycolysis enhances damage through TRPM7 histone lactylation

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2025-08-10 DOI:10.1016/j.taap.2025.117508

Shan Hu , Guiqing Liu , Haiyan Xiang , Jun Shao , Wanqi Lan , Chao Luo , Yonggang Shi , Wu Liu , Congcong Li , Yanhua Tang , Juesheng Yang

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引用次数: 0

Abstract

Background

Myocardial ischemia-reperfusion (I/R) is pivotal in myocardial infarction. Transient receptor potential melastatin 7 (TRPM7) plays an instrumental role in sustaining intracellular ion concentration and osmotic pressure. This study aimed to explore the function and mechanism of TRPM7 in the myocardial I/R model.

Methods

AC16 cardiomyocytes were exposed to hypoxia for 4 h and reoxygenated for 2, 4, 6, 8, and 12 h (H/R1 to H/R5). Cellular functions were evaluated using the MTT assay and flow cytometry. Protein expression was assessed by western blotting. Metabolic variations were detected with pyruvate and lactate kits. Chromatin Immunoprecipitation assays elucidated transcriptional regulation. A myocardial I/R model was constructed, and a TRPM7 inhibitor was administered in the corresponding group; immunohistochemistry, HE staining, and TUNEL assays were conducted for tissue-level detection.

Results

The findings revealed a significant decline in cell survival rates, and an increase in apoptosis and TRPM7 expression of AC16 cardiomyocytes under hypoxia/reoxygenation (H/R) conditions, with peak effects in the H/R3 condition. Silencing TRPM7 significantly reversed H/R-induced Ca²⁺ influx, cell survival rates, and apoptosis. Metabolic analyses indicated an upregulation of glycolysis in AC16 cardiomyocytes under the early stage of H/R, evidenced by elevated glycolysis-related proteins, pyruvate, and lactate levels, and the glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) inhibited the expression of TRPM7. Subsequent assays showed that H/R-induced glycolysis promoted TRPM7 transcription through histone lactylation, a finding corroborated by the in vivo I/R model.

Conclusions

This study highlighted that histone lactylation could be a potential therapeutic target for modulating TRPM7 expression and mitigating I/R injury.

查看原文本刊更多论文

心肌缺血/再灌注诱导糖酵解通过TRPM7组蛋白乳酸化增强损伤。

背景：心肌缺血再灌注（I/R）是心肌梗死的关键。瞬时受体电位美拉他汀7 （TRPM7）在维持细胞内离子浓度和渗透压中起重要作用。本研究旨在探讨TRPM7在心肌I/R模型中的作用及机制。方法：AC16心肌细胞缺氧4 h，再充氧2、4、6、8和12 h （h /R1至h /R5）。采用MTT法和流式细胞术评价细胞功能。western blotting检测蛋白表达。用丙酮酸和乳酸试剂盒检测代谢变化。染色质免疫沉淀试验阐明了转录调控。建立心肌I/R模型，给予TRPM7抑制剂；采用免疫组化、HE染色、TUNEL等方法进行组织水平检测。结果：缺氧/再氧化（H/R）条件下AC16心肌细胞的细胞存活率显著下降，细胞凋亡和TRPM7表达增加，H/R3条件下影响最大。沉默TRPM7可显著逆转H/ r诱导的Ca2+内流、细胞存活率和凋亡。代谢分析表明，H/R早期AC16心肌细胞糖酵解上调，糖酵解相关蛋白、丙酮酸和乳酸水平升高，糖酵解抑制剂2-脱氧-d-葡萄糖（2-DG）抑制TRPM7的表达。随后的实验表明，H/R诱导的糖酵解通过组蛋白乳酸化促进TRPM7的转录，这一发现得到了体内I/R模型的证实。结论：本研究强调组蛋白乳酸化可能是调节TRPM7表达和减轻I/R损伤的潜在治疗靶点。

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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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.