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Oxidized LDL stimulates PKM2-mediated mtROS production and phagocytosis
Jue Zhang1, Jackie Chang1, Vaya Chen1
1Versiti Blood Research Institute, Milwaukee, WI, USA.
Abstract:
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.
Insights
Oxidized low-density lipoprotein (oxLDL) drives atherosclerosis by increasing macrophage particle uptake. This process involves CD36 receptor, mitochondrial reactive oxygen species (mtROS), and pyruvate kinase muscle 2 (PKM2) signaling.
Area of Science:
- Cardiovascular Biology
- Cellular Metabolism
- Immunology
Background:
- Oxidized low-density lipoprotein (oxLDL) promotes proatherogenic macrophage phenotypes, contributing to atherosclerosis.
- Mitochondrial reactive oxygen species (mtROS) are implicated in atherosclerosis, but their induction mechanisms and cellular effects are unclear.
- Macrophage phagocytosis is crucial for homeostasis but dysregulation leads to foam cell formation, a hallmark of atherosclerosis.
Purpose of the Study:
- To elucidate the mechanisms by which oxLDL induces mtROS production and enhances macrophage phagocytosis.
- To identify the signaling pathways involved in oxLDL-mediated cellular dysfunction in macrophages.
- To investigate the role of mtROS and specific signaling molecules in promoting phagocytosis in atherogenic macrophages.
Main Methods:
- Macrophages were treated with oxLDL, and phagocytic activity was assessed.
- Cd36-null macrophages and siRNA knockdown of pyruvate kinase muscle 2 (PKM2) were used to investigate genetic contributions.
- Mitochondrial translocation of PKM2 was analyzed using specific inhibitors and knockdown techniques.
- Atherosclerosis-prone Apoe-null mice on high-fat and chow diets were used for in vivo validation.
Main Results:
- Oxidized low-density lipoprotein (oxLDL) significantly increased macrophage particle ingestion, dependent on CD36 receptor and mtROS production.
- In vivo studies showed elevated mtROS and phagocytic activity in aortic foamy macrophages of atherosclerosis-prone mice on a high-fat diet.
- A novel pathway was identified where oxLDL/CD36 interaction promotes mitochondrial translocation of PKM2, leading to increased mtROS and phagocytosis.
Conclusions:
- A novel oxLDL-CD36-PKM2 signaling axis stimulates mtROS production and phagocytosis in atherogenic macrophages.
- This pathway highlights a critical mechanism linking lipid oxidation, mitochondrial dysfunction, and macrophage-driven atherosclerosis.
- Targeting this pathway may offer therapeutic strategies for atherosclerosis treatment.
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