Ox‐LDL promotes M1‐like polarization of macrophages through the miR‐21‐5p/SKP2/EP300 pathway

Oxidized low‐density lipoprotein (ox‐LDL) mediated inflammatory damage, which possibly induces atherosclerosis (AS); however, the role of miRNA in this process has rarely been reported. In this paper, we study the ox‐LDL‐related endothelial cell damage and changes of macrophages. The bioinformatics method was used to analyze the expression changes of miRNA in AS patients, luciferase assay was used to study the interaction of protein and miRNA, and co‐IP and ubiquitination experiments were used to analyze protein interaction. Flow cytometry was used to detect the polarization of macrophages. Database analysis showed that the expression of miR‐21‐5p was upregulated in AS patients. Luciferase assay showed that miR‐21‐5p can bind to SKP2 and subsequently influence ubiquitination of EP300. Overexpression of EP300 strengthens the HMGB1‐induced acetylation and subsequently mediates the dissociation of HMGB1 from SIRT1, and thus HMGB1 could be secreted outside the cell. The HMGB1 released from endothelial cells can promote macrophage M1 polarization. This study shows that ox‐LDL activates the SKP2/EP300 pathway through promoting upregulation of miR‐21‐5p, thereby acetylating and secreting HMGB1 outside the endothelium, subsequently enhancing macrophage polarization to further stabilize the inflammation situation.