MicroRNA-761 modulates foam cell formation and inflammation through autophagy in the progression of atherosclerosis.

Abstract

Macrophage-derived foam cells formation is the initial stage of atherosclerosis, and lipid-laden macrophage accumulation is also considered as the symbol of unstable plaque. Autophagy is a subcellular process responsible for the degradation of damaged organelles and aggregated proteins in cells (Grootaert in Oxid Med Cell Longev: 7687083, 2018). Macrophage autophagy plays an important role in atherosclerosis under various stress conditions, and microRNAs are involved in this complicated process. The present study was programmed to explore the effects of microRNA-761 on macrophage-derived foam cell formation, focusing on the role of autophagy in this pathological process. The differentiated human THP-1 macrophages were used in the study. THP-1-derived macrophages were treated with miR-761 mimics or inhibitors and cultured with oxidized low-density lipoprotein to mimic the lipid-rich environment in blood vessel. The expression of miR-761 and mRNA levels of IL-1β and IL-18 were analyzed by quantitative real-time PCR. The effect of miR-761 on autophagy was evaluated by the protein levels of Beclin1, p62/SQSTM1, microtubule-associated protein light chain 3, mammalian target of rapamycin (mTOR), and unc-51-like autophagy activating kinase 1 (ULK1), determined by immunoblot and autophagic flux detected by fluorescent staining. The secretion of IL-1β and IL-18 was tested by enzyme-linked immunosorbent reaction kit. Lipid accumulation in foam cells was detected by oil red "O" staining. We demonstrated that miR-761 was able to repress foam cell formation and reduce the production of atherogenic inflammatory cytokines IL-1β and IL-18 in an autophagy-dependent manner in atherosclerosis, possibly via mTOR-ULK1 signaling pathway. In summary, we described an athero-protective function of miR-761 in macrophages incubated with excess ox-LDL and identified an important novel modulator of mTOR signaling and autophagy in macrophage-derived foam cells. This finding may provide a potential target for the prevention and early treatment in high-risk group of atherosclerosis.