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.
Authors
- A. Wayne Orr (ORCID: https://orcid.org/0000-0002-2377-213X)
- Ankan Gupta (ORCID: https://orcid.org/0000-0003-0111-6294)
- Weiguo Cui (ORCID: https://orcid.org/0000-0003-1562-9218)
- Shan Song (ORCID: https://orcid.org/0000-0002-2841-2213)
- James Traylor (ORCID: https://orcid.org/0000-0002-7119-6333)
- Mark Castleberry (ORCID: https://orcid.org/0000-0002-7916-5451)
- Ashley K. Brown (ORCID: https://orcid.org/0000-0002-1320-9327)
- Moua Yang (ORCID: https://orcid.org/0000-0001-6340-457X)
- Cyrine Ben Dhaou (ORCID: https://orcid.org/0000-0001-5126-8195)
- Wenxin Huang (ORCID: https://orcid.org/0000-0002-9015-5107)
- Yan-Qing Ma (ORCID: https://orcid.org/0000-0001-5795-3791)
- Jackie Chang (ORCID: https://orcid.org/0000-0002-7821-3167)
- M. A. Beg (ORCID: https://orcid.org/0000-0002-3598-894X)
- Jacek Zielonka (ORCID: https://orcid.org/0000-0002-2524-0145)
- Lance Vick (ORCID: https://orcid.org/0000-0001-9807-1947)
- Brian C. Smith (ORCID: https://orcid.org/0000-0001-6330-2768)
- Jieqing Zhu (ORCID: https://orcid.org/0000-0003-4508-4263)
- Heng Zhang (ORCID: https://orcid.org/0000-0002-6580-2464)
- Ziyu Zhang (ORCID: https://orcid.org/0000-0002-1982-112X)
- Jue Zhang (ORCID: https://orcid.org/0000-0001-8331-2496)
- Zhen Xu (ORCID: https://orcid.org/0000-0002-3542-1417)
- Yiliang Chen (ORCID: https://orcid.org/0000-0001-9786-8305)
- Wen Dai
- Erin Yttre
- Wenjing Chen (ORCID: https://orcid.org/0000-0002-9824-4809)
- Yaxin Wang (ORCID: https://orcid.org/0000-0003-0695-3542)
Institutions
- Hebei Medical University (CN)
- Northwestern University (US)
- Medical College of Wisconsin (US)
- Bloodworks Northwest (US)
- Versiti Blood Center of Wisconsin (US)
- Louisiana State University Health Sciences Center Shreveport (US)
Publication Details
- Journal
- Journal of Lipid Research
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1016/j.jlr.2025.100809
- Citations
- 8
- Primary Topic
- Adenosine and Purinergic Signaling
- Type
- article
- Field-Weighted Citation Impact
- 8.94
Funders
- American Heart Association
- National Heart, Lung, and Blood Institute