APE1 inhibits foam cell formation from macrophages via LOX1 suppression

Macrophage activation and massive foam cell formation are key events in the development of Atherosclerosis (AS). Apurinic apyrimidinic endonuclease 1/Redox factor-1 (APE1) is an enzyme responsible for DNA repair and redox regulation. Recent studies indicate that APE1 is also involved in inflammatory response. We sought to explore its effect on oxidized low-density lipoprotein (oxLDL) induced macrophage activation and foam cell formation.

Human macrophage cell line THP-1 cells were cultured and treated with oxLDL. The mRNA and protein levels of inflammatory markers for macrophage activation were measured. Foam cell formation was detected by Oil red O staining. Meanwhile the major cellular receptors responsible for oxLDL uptake and efflux were detected. Chromatin immunoprecipitation-quantitative real time PCR (ChIP-qPCR) and dual luciferase reporter assays were performed to identify the molecular mechanisms through which APE1 affects macrophage activation and foam cell formation.

Aberrant APE1 expression dramatically decreases the mRNA and protein of oxLDL-induced inflammatory molecules in THP-1 cells, accompanied by significantly inhibited foam cell formation. Western blot assay showed that down-regulation of LOX1, a receptor of oxLDL, is responsible for the inhibitory effect of APE1 on oxLDL induced macrophage inflammation. ChIP-qPCR assay showed that APE1 inhibits binding of the LOX1 promoter to its transcription factor Oct1, leading to suppression of LOX1.

Our data confirm the anti-inflammatory properties of APE1 and for the first-time report that APE1 suppresses foam cell formation from macrophages via the oxLDL receptor LOX1. This finding indicates that APE1 can be a therapeutic target for AS prevention.