Wang Yihua, Yue Qiang, Song Xiurong, Du Wei, Liu Rui
Department of Cardiovascular Medicine, Baotou City Center Hospital, Baotou City, 014040, Inner Mongolia, China.
Department of Anesthesiology, Donghe District, Baotou City Center Hospital, No.61, Huancheng Road, Baotou City, 014040, Inner Mongolia, China.
J Cardiovasc Transl Res. 2025 Jun 11. doi: 10.1007/s12265-025-10628-9.
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, Fe, 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.
心肌缺血再灌注损伤（MIRI）是心肌梗死的一种损伤机制，与铁死亡和糖酵解有关。糖酵解产生的乳酸会促进蛋白质乳酸化。本研究旨在探讨MIRI中糖酵解、铁死亡和GPX4乳酸化之间的相关性。缺氧/复氧（H/R）增加了H9C2细胞中的葡萄糖摄取、乳酸生成、细胞外酸化率（ECAR）、氧消耗率（OCR）、乳酸脱氢酶（LDH）释放、脂质活性氧（ROS）、铁、谷胱甘肽（GSH）、丙二醛（MDA）含量以及细胞凋亡，并降低了GSH水平，提示H/R促进了糖酵解和铁死亡。2-脱氧葡萄糖（2-DG）处理减轻了H/R诱导的损伤，而乳酸处理则加重了损伤。此外，2-DG抑制了GPX4在K218和K228位点的乳酸化，并提高了其蛋白质稳定性。GPX4过表达减轻了H/R引起的损伤，并减轻了心肌损伤，减少了MIRI大鼠心脏组织中心肌细胞的铁死亡。总之，GPX4乳酸化促进了H/R诱导的心肌细胞损伤，并加重了大鼠的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。
