Targeting the ApoB100-ENO1 interaction with engineered peptides attenuates atherosclerotic inflammation and plaque progression

초록

BACKGROUND: Atherosclerosis, a chronic inflammatory disease, presents significant "residual risk" even with effective lipid-lowering therapies, primarily due to persistent vascular inflammation. Apolipoprotein B100 (ApoB100) acquires pro-inflammatory properties upon modification and binds to cell-surface enolase 1 (ENO1), an immune modulator upregulated in inflammatory conditions. This interaction induces inflammatory responses via NF-kappa B activation. Targeting the ApoB100-ENO1 interaction may offer a novel strategy to reduce vascular inflammation and atherosclerosis progression. METHODS: We developed PP3m, a stabilized ApoB100-derived peptide, to selectively inhibit the ApoB100-ENO1 interaction. Single-cell RNA sequencing (scRNA-seq) data from human atherosclerotic plaques were reanalyzed to characterize ENO1 expression in myeloid cells. In vitro, PP3m's anti-inflammatory effects were evaluated across various macrophage models stimulated by diverse inflammatory stimuli. Outcomes included cytokine secretion, inflammatory gene expression, foam cell formation, oxidized low-density lipoprotein (oxLDL) uptake, and signaling pathways activation. In vivo, Ldlr-/- mice fed an atherogenic diet were treated with PP3m to evaluate its effects on atherosclerosis progression, macrophage accumulation, and systemic inflammation. RESULTS: scRNA-seq analysis revealed that human atherosclerotic plaques harbor significantly more ENO1 macrophages, with ENO1 expression enriched in CD68+ M1 macrophages. Atherogenic stimuli induced ENO1 translocation to the plasma membrane in macrophages. In vitro, PP3m significantly attenuated inflammatory responses by suppressing IL-6 and CXCL8 secretion, reducing M1 polarization, and dose-dependently inhibiting oxLDL-induced foam cell formation and uptake. In vivo, PP3m reduced aortic lesion area, lipid content, and collagen deposition, accompanied by decreased macrophage accumulation in plaques and lower circulating pro-inflammatory cytokines. Importantly, these effects were independent of changes in plasma lipid profiles. CONCLUSIONS: The ApoB100-ENO1 axis is a critical driver of macrophage-mediated inflammation in atherosclerosis. The novel peptide PP3m effectively inhibits this interaction, reducing vascular inflammation and plaque progression without altering lipid levels. PP3m represents a promising therapeutic candidate for cardiovascular disease by targeting residual inflammatory risk through a lipid-independent mechanism.

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