An agomir of miR-144-3p accelerates plaque formation through impairing reverse cholesterol transport and promoting pro-inflammatory cytokine production.
An agomir of miR-144-3p accelerates plaque formation through impairing reverse cholesterol transport and promoting pro-inflammatory cytokine production.
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DOI：
10.1371/journal.pone.0094997
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Wang Q
中科院分区：
文献类型：
--
作者：
Hu YW;Hu YR;Zhao JY;Li SF;Ma X;Wu SG;Lu JB;Qiu YR;Sha YH;Wang YC;Gao JJ;Zheng L;Wang Q
ATP结合盒转运蛋白A1（ABCA 1）介导胆固醇和磷脂流出到贫脂载脂蛋白，然后形成新生HDL，这是胆固醇逆向转运（RCT）机制的关键步骤。虽然一系列microRNA（miRNAs）已被鉴定为脂质代谢的有效转录后调节因子，但它们对ABCA 1功能的影响及其相关机制尚不清楚。基于生物信息学分析和荧光素酶报告基因测定的结果，ABCA 1被鉴定为miR-144- 3 p的潜在靶点，并且在用miR-144- 3 p模拟物转染细胞后下调，如通过实时PCR和western blot观察到的。此外，miR-144- 3 p模拟物（agomir）在体内和体外增强炎症因子（包括IL-1β、IL-6和TNF-α）的表达，抑制THP-1巨噬细胞源性泡沫细胞中的胆固醇流出，降低HDL-C循环，并在体内损害RCT，导致apoE−/−小鼠动脉粥样硬化的病理进展加速。临床研究还显示，在AMI受试者中，循环miR-144- 3 p与血清CK、CK-MB、LDH和AST呈正相关。我们的研究结果清楚地表明，miR-144- 3 p是调节胆固醇稳态和炎症反应所必需的，支持其作为动脉粥样硬化的潜在治疗靶点和有前途的AMI诊断生物标志物的效用。
ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins, which then form nascent HDL, a key step in the mechanism of reverse cholesterol transport (RCT). While a series of microRNAs (miRNAs) have been identified as potent post-transcriptional regulators of lipid metabolism, their effects on ABCA1 function and associated mechanisms remain unclear. ABCA1 was identified as a potential target of miR-144-3p, based on the results of bioinformatic analysis and the luciferase reporter assay, and downregulated after transfection of cells with miR-144-3p mimics, as observed with real-time PCR and western blot. Moreover, miR-144-3p mimics (agomir) enhanced the expression of inflammatory factors, including IL-1β, IL-6 and TNF-α, in vivo and in vitro, inhibited cholesterol efflux in THP-1 macrophage-derived foam cells, decreased HDL-C circulation and impaired RCT in vivo, resulting in accelerated pathological progression of atherosclerosis in apoE−/− mice. Clinical studies additionally revealed a positive correlation of circulating miR-144-3p with serum CK, CK-MB, LDH and AST in subjects with AMI. Our findings clearly indicate that miR-144-3p is essential for the regulation of cholesterol homeostasis and inflammatory reactions, supporting its utility as a potential therapeutic target of atherosclerosis and a promising diagnostic biomarker of AMI.
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DOI：
10.1161/atvbaha.108.178681
发表时间：
2009-02
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Jahangiri A;de Beer MC;Noffsinger V;Tannock LR;Ramaiah C;Webb NR;van der Westhuyzen DR;de Beer FC
通讯作者：
de Beer FC
影响因子：
37.8
作者：
Inoue, S;Egashira, K;Takeshita, A
通讯作者：
Takeshita, A
影响因子：
5.3
作者：
Hu, Yan-Wei;Ma, Xin;Tang, Chao-Ke
通讯作者：
Tang, Chao-Ke
影响因子：
--
作者：
Barter, Philip
通讯作者：
Barter, Philip
影响因子：
4.8
作者：
Iqbal, J;Anwar, K;Hussain, MM
通讯作者：
Hussain, MM