Lactate-Induced Mitochondrial Calcium Uptake 3 Aggravates Myocardial Ischemia–Reperfusion Injury by Promoting Neutrophil Extracellular Trap Formation

作者：Hongru Zhang, Lei Liu, Chuchu Shen, Xinxue Jiang, Jing Liu, Jing Chen, Sen-Lei Xu, Yanfei Mo · 发表于：Research · 年份：2025 · DOI：10.34133/research.0705 · 被引用次数：19 · 研究领域：Neutrophil, Myeloperoxidase and Oxidative Mechanisms、S100 Proteins and Annexins、Nitric Oxide and Endothelin Effects

Background: Ischemic heart disease is a leading cause of mortality and disability worldwide among cardiovascular conditions. Myocardial ischemia–reperfusion injury (MIRI) occurs following percutaneous coronary intervention, during which neutrophils generate neutrophil extracellular traps (NETs) in response to injury. This study aims to elucidate the mechanisms underlying NET activation and its impact on MIRI. Methods: Sham and MIRI rat models were established. Various techniques, including enzyme-linked immunosorbent assay, hematoxylin and eosin staining, Masson staining, and transmission electron microscopy, were used to assess endothelial cell injury and myocardial tissue inflammation. Immunofluorescence was employed to evaluate NET activation in tissues, peripheral blood neutrophils, and protein colocalization. MitoTracker and ER-Tracker staining were conducted to assess the formation of mitochondria-associated membranes (MAMs). Extracted NETs were applied to conduct microvascular endothelial cell tube formation assay and flow cytometry. RNA-sequencing and immunoprecipitation–mass spectrometry were applied to determine the key regulators. Flow cytometry and Western blot were used to assess Ca 2+ and mitophagy levels in neutrophils. Deoxyribonuclease I, NET inhibitor, was injected into MIRI rats to evaluate the in vivo effects of NET modulation on MIRI severity. Results: MIRI was often accompanied by cardiac microvascular endothelial cell (CMEC) injury and inflammation. Lac...