氧化LDL刺激pkm2介导的mtROS产生和吞噬。

IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Journal of Lipid Research Pub Date : 2025-05-01 Epub Date: 2025-04-16 DOI:10.1016/j.jlr.2025.100809
Jue Zhang, Jackie Chang, Vaya Chen, Mirza Ahmar 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 Kaye Brown, Zhen Xu, Yan-Qing Ma, Brian C Smith, Jacek Zielonka, James G Traylor, Cyrine Ben Dhaou, A Wayne Orr, Weiguo Cui, Yiliang Chen
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引用次数: 0

摘要

氧化低密度脂蛋白(oxLDL)促进巨噬细胞的致动脉粥样硬化表型,加速动脉粥样硬化的进展。我们之前的研究表明,oxLDL与其受体CD36结合,刺激线粒体活性氧(mtROS),这在动脉粥样硬化的发展中至关重要。然而,mtROS诱导的机制及其对巨噬细胞功能的影响仍然知之甚少。巨噬细胞依靠吞噬作用清除病原体、凋亡细胞或其他颗粒,这一过程对组织稳态至关重要。颗粒摄取失调或过量是吞噬作用的关键步骤,可导致脂质超载和泡沫细胞形成,这是动脉粥样硬化的标志。在这项研究中,我们发现用oxLDL预处理的巨噬细胞表现出颗粒摄入增加,Cd36-null巨噬细胞的吞噬反应显著减弱。进一步的研究表明,氧化低密度脂蛋白诱导的吞噬依赖于mtROS,因为它们的抑制抑制了这一过程。在体内,与鼠粮相比,高脂肪饮食中易发生动脉粥样硬化的apoe缺失小鼠表现出更高的mtROS水平和主动脉泡沫巨噬细胞的吞噬活性增强,支持mtROS在促进病变巨噬细胞吞噬中的作用。在机制上,我们发现了一种新的信号通路,即oxLDL/CD36相互作用诱导胞质酶丙酮酸激酶肌2 (PKM2)向线粒体的易位。使用siRNA敲低或特定化学抑制剂破坏PKM2线粒体易位可减少mtROS的产生并减弱氧化低密度脂蛋白诱导的吞噬作用。总之,我们的研究结果揭示了一种新的oxLDL-CD36-PKM2信号轴,该信号轴驱动致动脉粥样硬化巨噬细胞的mtROS产生和吞噬。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Oxidized LDL stimulates PKM2-mediated mtROS production and phagocytosis.

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 mitochondria. Disruption of PKM2 mitochondrial translocation using siRNA knockdown or a specific chemical inhibitor reduced mtROS production and attenuated oxLDL-induced phagocytosis. In conclusion, our findings reveal a novel oxLDL-CD36-PKM2 signaling axis that drives mtROS production and phagocytosis in atherogenic macrophages.

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来源期刊
Journal of Lipid Research
Journal of Lipid Research 生物-生化与分子生物学
CiteScore
11.10
自引率
4.60%
发文量
146
审稿时长
41 days
期刊介绍: The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.
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