miR-223 Inhibits Lipid Deposition and Inflammation by Suppressing Toll-Like Receptor 4 Signaling in Macrophages

Abstract

Atherosclerosis and its complications rank as the leading cause of death with the hallmarks of lipid deposition and inflammatory response. MicroRNAs (miRNAs) have recently garnered increasing interests in cardiovascular disease. In this study, we investigated the function of miR-223 and the underlying mechanism in atherosclerosis. In the atherosclerotic ApoE−/− mice models, an obvious increase of miR-223 was observed in aortic atherosclerotic lesions. In lipopolysaccharide (LPS) activated macrophages, its expression was decreased. The miR-223 overexpression significantly attenuated macrophage foam cell formation, lipid accumulation and pro-inflammatory cytokine production, which were reversed by anti-miR-223 inhibitor transfection. Mechanism assay corroborated that miR-223 negatively regulated the activation of the toll-like receptor 4 (TLR4)-nuclear factor-κB (NF-κB) pathway. Pretreatment with a specific inhibitor of NF-κB (pyrrolidinedithiocarbamate, PDTC) strikingly abrogated miR-223 silence-induced lipid deposition and inflammatory cytokine production. Furthermore, PI3K/AKT was activated by miR-223 up-regulation. Pretreatment with PI3K/AKT inhibitor LY294002 strikingly ameliorated the inhibitory effects of miR-223 on the activation of TLR4 and p65, concomitant with the increase in lipid deposition and inflammatory cytokine production. Together, these data indicate that miR-223 up-regulation might abrogate the development of atherosclerosis by blocking TLR4 signaling through activation of the PI3K/AKT pathway, and provides a promising therapeutic avenue for the treatment of atherosclerosis.

MiR‐181a inhibits vascular inflammation induced by ox‐LDL via targeting TLR4 in human macrophages

“…MiR‐146a has been reported to inhibit ox‐LDL‐induced inflammatory response through targeting TLR4 (Yang et al, ). miR‐223 can repress lipid accumulation and inflammation through suppressing TLR4 signaling in macrophages (Wang, Bai et al, ). Additionally, miR‐21 has been reported to attenuate inflammatory response by targeting TLR4 (Feng et al, ).…”

Inflammation‐regulatory microRNAs: Valuable targets for intracranial atherosclerosis

“…Unlike miR‐27a/b, miR‐223 could indirectly enhance ABCA1 expression levels and accelerate cholesterol efflux, which could sustain cellular cholesterol homeostasis (Vickers et al, ). These results identified a reverse role of miR‐223 in dominating the atherosclerosis progression by affecting inflammatory thrombosis process (Li, Tan, et al, ; Li et al, ; Vickers et al, ; Wang, Bai, et al, ). However, miR‐223 released from platelet microvesicles could directly downregulate the expressions of insulin‐like growth factor 1 receptor (IGF‐1R) within vascular endothelial cells as well, thereby facilitating endothelial cell apoptosis stimulated by AGEs (Pan et al, ).…”

“…Circulating miR‐223 biomarker attracts so much attention in virtue of the importance in regulating ICAS pathology by different potential pathways (Novak et al, ; Shan et al, ). miR‐223 could directly suppress the expression levels of ICAM‐1 in vascular endothelial cells via blocking NF‐κB signaling pathway (Li, Tan, et al, ), and this miRNA could further impair the accumulation of lipid and the formation of foam cells through impacting NF‐κB pathway in macrophages (Wang, Bai, et al, ). Upregulation of miR‐223 could also directly inhibit tissue factor (TF) expressions in vascular endothelial cells and repress the pro‐coagulant activation of TF (Li et al, ).…”

Diagnostic and theranostic microRNAs in the pathogenesis of atherosclerosis

“…As deletion of endothelial‐specific miR‐424, miR‐322 and miR‐503, HUVECs showed angiogenic response with inflammation‐induced angiogenesis . MiR‐223 is another inhibitor of lipid accumulation and inflammation that promotes endothelial cell apoptosis by blocking TLR4 (Figure C) and IGF‐1R …”