Hypoxia/reoxygenation-induced Glycolysis Mediates Myocardial Ischemia-reperfusion Injury Through Promoting the Lactylation of GPX4.

IF 2.4 3区医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS

Journal of Cardiovascular Translational Research Pub Date : 2025-06-11 DOI:10.1007/s12265-025-10628-9

Yihua Wang, Qiang Yue, Xiurong Song, Wei Du, Rui Liu

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Abstract

Myocardial ischemia-reperfusion injury (MIRI) is an injury mechanism of myocardial infarction, related to ferroptosis and glycolysis. Lactate produced by glycolysis promotes protein lactylation. This study aimed to investigate the correlation between glycolysis, ferroptosis, and GPX4 lactylation in MIRI. Hypoxia/reoxygenation (H/R) increased glucose uptake, lactate production, ECAR, OCR, LDH release, lipid ROS, Fe²⁺, GSH, MDA contents, and cell apoptosis, and decreased GSH level in the H9C2 cells, suggesting H/R promoted glycolysis and ferroptosis. 2-DG treatment relieved the H/R-induced injury, while lactate treatment aggravated it. Besides, 2-DG suppressed lactylation of GPX4 at K218 and K228 sites and increased its protein stability. GPX4 overexpression relieved the injury caused by H/R, and alleviated cardiac injury, decreased cardiomyocyte ferroptosis in heart tissues of MIRI rats. In conclusion, GPX4 lactylation facilitated H/R-induced cardiomyocyte injury and aggravated MIRI in rats. Our findings provided new insight into targeting glycolysis and GPX4 lactylation as therapeutic strategies of MIRI.

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缺氧/再氧诱导糖酵解通过促进GPX4的乳酸化介导心肌缺血再灌注损伤。

心肌缺血再灌注损伤（MIRI）是心肌梗死的一种损伤机制，与铁下垂和糖酵解有关。糖酵解产生的乳酸促进蛋白质的乳酸化。本研究旨在探讨糖酵解、铁下垂和GPX4乳酸化在MIRI中的相关性。缺氧/再氧化（H/R）增加了H9C2细胞的葡萄糖摄取、乳酸生成、ECAR、OCR、LDH释放、脂质ROS、Fe2+、GSH、MDA含量和细胞凋亡，降低了GSH水平，提示H/R促进糖酵解和铁凋亡。2-DG处理可减轻H/ r诱导的损伤，乳酸处理可加重H/ r诱导的损伤。此外，2-DG抑制了GPX4在K218和K228位点的乳酸化，提高了GPX4蛋白的稳定性。GPX4过表达可减轻H/R损伤，减轻心肌损伤，降低MIRI大鼠心脏组织心肌细胞下垂。综上所述，GPX4乳酸化促进了H/ r诱导的大鼠心肌细胞损伤，加重了MIRI。我们的研究结果为靶向糖酵解和GPX4乳酸化作为MIRI的治疗策略提供了新的见解。

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

Journal of Cardiovascular Translational Research CARDIAC & CARDIOVASCULAR SYSTEMS-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

6.10

自引率

2.90%

发文量

148

审稿时长

6-12 weeks

期刊介绍： Journal of Cardiovascular Translational Research (JCTR) is a premier journal in cardiovascular translational research. JCTR is the journal of choice for authors seeking the broadest audience for emerging technologies, therapies and diagnostics, pre-clinical research, and first-in-man clinical trials. JCTR''s intent is to provide a forum for critical evaluation of the novel cardiovascular science, to showcase important and clinically relevant aspects of the new research, as well as to discuss the impediments that may need to be overcome during the translation to patient care.