Silencing of IGF2BP1 restrains ox-LDL-induced lipid accumulation and inflammation by reducing RUNX1 expression and promoting autophagy in macrophages

Atherosclerosis (AS) is a chronic inflammatory disease with the formation and accumulation of macrophage-derived foam cells in the subendothelial space of blood vessels as one major characteristic. Insulin-like growth factor 2 messenger RNA (mRNA) binding protein 1 (IGF2BP1) is an RNA-binding factor and its elevation has been reported to be associated with macrophage infiltration into the atherosclerotic vascular wall. This study aims to investigate the roles of IGF2BP1 in AS-associated foam cell formation. Herein, ApoE-/- mice fed with high-fat diet developed atherosclerotic lesions in the aorta, where IGF2BP1 expression was upregulated and autophagy was impaired. IGF2BP1 expressed in F4/80+ macrophages and coexisted with p62. In vitro, IGF2BP1 expression was upregulated in RAW264.7 macrophages exposed to oxidized low-density lipoprotein (ox-LDL) (100 μg/ml). Interestingly, silencing of IGF2BP1 ameliorated ox-LDL-induced lipid accumulation and inflammation, and enhanced autophagic flux in macrophages. Furthermore, the expression of RUNX family transcription factor 1 (RUNX1), a gene that is able to inhibit autophagy in multiple cell types, was elevated in atherosclerotic aortas and in ox-LDL-treated macrophages. In addition, RNA immunoprecipitation results revealed that IGF2BP1 is bound to RUNX1 mRNA. Alterations induced by IGF2BP1 knockdown in ox-LDL-treated macrophages were abolished by RUNX1 overexpression. Furthermore, after autophagy inhibitor 3-methyladenine administration, silencing of IGF2BP1-reduced lipid accumulation and inflammation were recovered in RAW264.7 cells. In summary, our study demonstrated that silencing of IGF2BP1 restrained ox-LDL-induced lipid accumulation and inflammation by reducing RUNX1 expression and facilitating autophagy in macrophages. IGF2BP1/RUNX1 axis may be considered as a potential therapeutic target in AS.