Fu-Ju Tian1, Li-Na An2, Guo-Kun Wang1, Jia-Qi Zhu2, Qing Li1, Ying-Ying Zhang3, An Zeng1, Jun Zou1, Rong-Fang Zhu1, Xiao-Shuai Han1, Nan Shen1, Huang-Tian Yang1, Xian-Xian Zhao2, Shuang Huang2, Yong-Wen Qin2, Qing Jing4. 1. The Key Laboratory of Stem Cell Biology, Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao-Tong University School of Medicine, 320 Yue-Yang Rd, Building 41, Room 227, Shanghai 200031, China. 2. Department of Cardiology, Changhai Hospital, Shanghai, China. 3. Department of Rheumatology, Huadong Hospital of Fudan University, Shanghai, China. 4. The Key Laboratory of Stem Cell Biology, Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao-Tong University School of Medicine, 320 Yue-Yang Rd, Building 41, Room 227, Shanghai 200031, China Department of Cardiology, Changhai Hospital, Shanghai, China qjing@sibs.ac.cn.
Abstract
AIM: MicroRNAs (miRNAs) play key roles in inflammatory responses of macrophages. However, the function of miRNAs in macrophage-derived foam cell formation is unclear. Here, we investigated the role of miRNAs in macrophage-derived foam cell formation and atherosclerotic development. METHODS AND RESULTS: Using quantitative reverse transcription-PCR (qRT-PCR), we found that the level of miR-155 expression was increased significantly in both plasma and macrophages from atherosclerosis (ApoE(-/-)) mice. We identified that oxidized low density lipoprotein (oxLDL) induced the expression and release of miR-155 in macrophages, and that miR-155 was required to mediate oxLDL-induced lipid uptake and reactive oxygen species (ROS) production of macrophages. Furthermore, ectopic overexpression and knockdown experiments identified that HMG box-transcription protein1 (HBP1) is a novel target of miR-155. Knockdown of HBP1 enhanced lipid uptake and ROS production in oxLDL-stimulated macrophages, and overexpression of HBP1 repressed these effects. Furthermore, bioinformatics analysis identified three YY1 binding sites in the promoter region of pri-miR-155 and verified YY1 binding directly to its promoter region. Detailed analysis showed that the YY1/HDAC2/4 complex negatively regulated the expression of miR-155 to suppress oxLDL-induced foam cell formation. Importantly, inhibition of miR-155 by a systemically delivered antagomiR-155 decreased clearly lipid-loading in macrophages and reduced atherosclerotic plaques in ApoE(-/-) mice. Moreover, we observed that the level of miR-155 expression was up-regulated in CD14(+) monocytes from patients with coronary heart disease. CONCLUSION: Our findings reveal a new regulatory pathway of YY1/HDACs/miR-155/HBP1 in macrophage-derived foam cell formation during early atherogenesis and suggest that miR-155 is a potential therapeutic target for atherosclerosis. Published on behalf of the European Society of Cardiology. All rights reserved.
AIM: MicroRNAs (miRNAs) play key roles in inflammatory responses of macrophages. However, the function of miRNAs in macrophage-derived foam cell formation is unclear. Here, we investigated the role of miRNAs in macrophage-derived foam cell formation and atherosclerotic development. METHODS AND RESULTS: Using quantitative reverse transcription-PCR (qRT-PCR), we found that the level of miR-155 expression was increased significantly in both plasma and macrophages from atherosclerosis (ApoE(-/-)) mice. We identified that oxidized low density lipoprotein (oxLDL) induced the expression and release of miR-155 in macrophages, and that miR-155 was required to mediate oxLDL-induced lipid uptake and reactive oxygen species (ROS) production of macrophages. Furthermore, ectopic overexpression and knockdown experiments identified that HMG box-transcription protein1 (HBP1) is a novel target of miR-155. Knockdown of HBP1 enhanced lipid uptake and ROS production in oxLDL-stimulated macrophages, and overexpression of HBP1 repressed these effects. Furthermore, bioinformatics analysis identified three YY1 binding sites in the promoter region of pri-miR-155 and verified YY1 binding directly to its promoter region. Detailed analysis showed that the YY1/HDAC2/4 complex negatively regulated the expression of miR-155 to suppress oxLDL-induced foam cell formation. Importantly, inhibition of miR-155 by a systemically delivered antagomiR-155 decreased clearly lipid-loading in macrophages and reduced atherosclerotic plaques in ApoE(-/-) mice. Moreover, we observed that the level of miR-155 expression was up-regulated in CD14(+) monocytes from patients with coronary heart disease. CONCLUSION: Our findings reveal a new regulatory pathway of YY1/HDACs/miR-155/HBP1 in macrophage-derived foam cell formation during early atherogenesis and suggest that miR-155 is a potential therapeutic target for atherosclerosis. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Dimitry A Chistiakov; Alexandra A Melnichenko; Veronika A Myasoedova; Andrey V Grechko; Alexander N Orekhov Journal: J Mol Med (Berl) Date: 2017-08-07 Impact factor: 4.599