miR-223 Inhibits Lipid Deposition and Inflammation by Suppressing Toll-Like Receptor 4 Signaling in Macrophages.
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.
Department of Cardiology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710004, China. wangjunms@stu.xjtu.edu.cn.
Jun
J
Wang
Department of Cardiology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710004, China. xiaojunbai@126.com.
Xiaojun
X
Bai
Department of Cardiology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710004, China. qiangsongxa@163.com.
Qiang
Q
Song
Department of Cardiology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710004, China. fenlingfan@163.com.
Fenling
F
Fan
Department of Cardiology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710004, China. zhihusx@163.com.
Zhi
Z
Hu
Department of Cardiology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710004, China. geshengcheng@163.com.
Gesheng
G
Cheng
Department of Cardiology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710004, China. zhangyushun@xjtu.edu.cn.
Yushun
Y
Zhang
D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D000067996:RAW 264.7 Cells; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
D015850:Interleukin-6; C544877:MIRN223 microRNA, mouse; D035683:MicroRNAs; D051197:Toll-Like Receptor 4
PI3K/AKT; TLR4; atherosclerosis; inflammatory; lipid accumulation; miR-223