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.

In silico Prediction of miRNA Interactions With Candidate Atherosclerosis Gene mRNAs

“…In human, it is known about 7000 miRNA and more than 20,000 genes, and it is unknown how many miRNA and genes from them participate in the development of atherosclerosis (Byrne et al, 2014;Toba et al, 2014;Lu et al, 2018;Liu et al, 2020;Shi et al, 2020). As a rule, in publications several miRNA and some candidate genes are studied, so the combination of such attempts is large (Wang C. et al, 2020;Wang M. et al, 2020;Zhang et al, 2020). Considering the limitations of existing prediction methods, we can say that the establishment of adequate miRNA markers for diseases is unrealistic using existing approaches in the coming years.…”

Autophagy, Pyroptosis, and Ferroptosis: New Regulatory Mechanisms for Atherosclerosis

“…Arsenic trioxide promoted autophagy and autophagosome-lysosome fusion by triggering the nuclear translocation of TFEB, thus preventing atherosclerosis ( Fang et al, 2021 ). MiR-761 regulates autophagy via the mTOR–ULK1 pathway and subsequently represses the production of inflammatory cytokines, as well as the formation of foam cells ( Wang C. et al, 2020 ), reflecting the critical role of macrophage autophagy in inflammatory resistance and foam cell formation. The activation of autophagy in monocytes also prevents plaque vulnerability and subsequent plaque rupture ( Cheng et al, 2015 ).…”

Regulation of autophagy by miRNAs in human diseases

“…miR-761 binds explicitly to mTOR and induces autophagy which also facilitates the downregulation of pro-inflammatory cytokines IL-1β and IL-18. Treatment of ox-LDL-treated THP-1 cells with miR-761 mimic and an autophagy inhibitor (Chloroquine) shows that the anti-inflammatory effect of miR-761 is heavily dependent upon autophagy flux [ 75 ]. Finally, a non-canonical mode of post-translational modification by miR-126-5p in human umbilical vein vascular endothelial (HUVEC) cells has broadened the spectrum of the effect of miRNAs in atherosclerosis.…”