Macrophage PIM1 Drives Atherosclerosis by Enhancing Foam Cell Formation Via CD36
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Background
Atherosclerosis is characterized by the buildup of fatty plaques that thicken and stiffen arterial walls. Macrophages (Mφs) significantly contribute to this process through their scavenger receptor CD36. PIM1 is a serine/threonine kinase known to modulate immune responses and cell metabolism. However, its role in Mφ lipid handling and atherogenesis is not well defined. This study examines the role of PIM1 in regulating CD36 expression and function in Mφs during foam cell formation and atherosclerosis progression.
Methods
We performed in vitro studies by treating murine peritoneal Mφs from Pim1 -/- and wild-type (WT) mice with oxidized low-density lipoprotein (oxLDL). We measured CD36, PIM1, and plaque-associated proteins and mRNA levels, oxLDL binding and uptake rates, as well as foam cell formation. For in vivo studies, we fed Mφ-specific PIM1-deficient ( Apoe -/- Lyz2 Cre/+ Pim1 fl/fl ) and their littermate control ( Apoe ⁻/⁻ Pim1 fl/fl ) mice a high-fat diet for 12 weeks. We then evaluated the plaque formation in their aortic sinuses and arches.
Results
Deletion of Pim1 in Mφs reduced CD36 protein expression by up to 96.7% compared to WT controls. This led to a 49.6% decrease in foam cell formation and a 25.5% reduction in cellular cholesterol after oxLDL treatment. Pharmacological inhibition of PIM kinase activity in WT Mφs also impaired oxLDL handling, with a 64.5% reduction in binding and a 57.9% in uptake. Bulk RNA-seq revealed that Pim1 deficiency downregulated PPARγ signaling. Treatment with a PPARγ agonist restored CD36 levels in the PIM1 knockdown Mφs, suggesting that PIM1 regulates CD36 through PPARγ. Moreover, PIM1 Mφ-specific deficiency caused a 69.4% reduction in atherosclerotic plaque formation.
Conclusion
PIM1 acts as a key upstream regulator of CD36 by enhancing PPARγ activity in Mφs. The PIM1-CD36 axis promotes oxLDL binding, uptake, and foam cell formation. Targeting the PIM1/PPARγ/CD36 pathway could offer new ways to modulate Mφ lipid metabolism and reduce atherosclerotic plaque progression.
Non-standard Abbreviations and Acronyms
ELISA: enzyme-linked immunosorbent assay; HFD: high-fat diet; Mφs: macrophages; MCP-1: monocyte chemoattractant protein-1; ORO: oil red O; oxLDL: oxidized low-density lipoprotein; PBS: phosphate-buffered saline; PPARγ: peroxisome proliferator-activated receptor gamma; WT: wild type.
