Oxidized LDL stimulates PKM2-mediated mtROS production and phagocytosis

作者：Jue Zhang, Jackie Chang, Vaya Chen, M. A. Beg, Wenxin Huang, Lance Vick, Yaxin Wang, Heng Zhang, Erin Yttre, Ankan Gupta, Mark Castleberry, Ziyu Zhang, Wen Dai, Jieqing Zhu, Shan Song, Moua Yang, Ashley K. Brown, Zhen Xu, Yan-Qing Ma, Brian C. Smith, Jacek Zielonka, James Traylor, Cyrine Ben Dhaou, A. Wayne Orr, Weiguo Cui, Yiliang Chen · 发表于：Journal of Lipid Research · 年份：2025 · DOI：10.1016/j.jlr.2025.100809 · 被引用次数：12 · 研究领域：Adenosine and Purinergic Signaling、Cardiovascular, Neuropeptides, and Oxidative Stress Research、Advanced Glycation End Products research

Oxidized low-density lipoprotein (oxLDL) promotes proatherogenic phenotypes in macrophages, accelerating the progression of atherosclerosis. Our previous studies demonstrated that oxLDL binds to its receptor CD36, stimulating mitochondrial reactive oxygen species (mtROS), which are critical in atherosclerosis development. However, the mechanisms underlying mtROS induction and their effects on macrophage cellular functions remain poorly understood. Macrophages rely on phagocytosis to clear pathogens, apoptotic cells, or other particles, a process critical for tissue homeostasis. Dysregulated or excessive particle ingestion, a key step in phagocytosis, can lead to lipid overloading and foam cell formation, a hallmark of atherosclerosis. In this study, we showed that macrophages pretreated with oxLDL exhibit increased particle ingestion, a phagocytic response significantly attenuated in Cd36-null macrophages. Further investigations revealed that oxLDL-induced phagocytosis depends on mtROS, as their suppression inhibited the process. In vivo, atherosclerosis-prone Apoe-null mice on a high-fat diet exhibited increased mtROS levels and enhanced phagocytic activity in aortic foamy macrophages compared to those from chow diet-fed mice, supporting a role of mtROS in promoting lesional macrophage phagocytosis. Mechanistically, we identified a novel signaling pathway whereby oxLDL/CD36 interaction induces the translocation of the cytosolic enzyme pyruvate kinase muscle 2 (PKM2) to mitoc...