Unc5b prevents macrophage-derived foam cell migration and promotes atherosclerotic development via the P53-cuproptosis signaling pathway

Abstract

Background: Atherosclerosis involves the buildup of macrophage-derived foam cells in the arterial intima. Facilitating the egress of these cells from plaques can significantly slow disease progression. The transmembrane receptor Unc5b, a vascular-specific axon guidance receptor, is upregulated in foam cells, and inhibits their migration from the plaques. However, the mechanisms underlying Unc5b's regulation of foam cell production and retention within plaques, along with its downstream signaling pathways, remain insufficiently understood.

Methods: We employed both a foam cell model and an ApoE-deficient mouse model of atherosclerosis to evaluate these effects. Western blotting, RT-PCR, wound healing assays, and immunofluorescence staining were performed to explore the role of Unc5b in foam cell migration.

Results: Unc5b played a role in advancing atherosclerosis by regulating the P53-cuproptosis pathway, thereby inhibiting the migration of foam cells. Stimulation of Raw264.7 cells with oxidized low-density lipoprotein (ox-LDL) resulted in increased cuproptosis and inflammation, impacting migration regulation. Macrophage-derived foam cell migration was prevented by Unc5b via the P53-cuproptosis signaling pathway. Notably, PFT-α (a P53 inhibitor) and VI (a Cu²⁺ chelator) counteracted the inhibitory effect of ox-LDL on migration. Similarly, upregulation of cuproptosis-related proteins was observed within the aortic sinus plaques of ApoE^-/- mice fed a hyperlipidemic diet. Importantly, the progression of atherosclerosis induced by a hyperlipidemic diet can be effectively reversed by PFT-α and VI.

Conclusion: These findings underscore Unc5b's role in promoting inflammation, inhibiting macrophage migration, and promoting atherosclerotic development via the P53-cuproptosis signaling pathway.

Keywords: Atherosclerosis; Cuproptosis; Macrophages; P53; Unc5b.