title: Elevated microRNA-155 promotes foam cell formation by targeting HBP1 in atherogenesis.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Fu-Ju
authors.initials: FJ
authors.lastname: Tian
authors.affiliation: Department of Cardiology, Changhai Hospital, Shanghai, China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: An
authors.affiliation: 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.
authors.forename: Guo-Kun
authors.initials: GK
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Changhai Hospital, Shanghai, China.
authors.forename: Jia-Qi
authors.initials: JQ
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Rheumatology, Huadong Hospital of Fudan University, Shanghai, China.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: An
authors.initials: A
authors.lastname: Zeng
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Zou
authors.affiliation: 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.
authors.forename: Rong-Fang
authors.initials: RF
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Xiao-Shuai
authors.initials: XS
authors.lastname: Han
authors.affiliation: 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.
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Huang-Tian
authors.initials: HT
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Changhai Hospital, Shanghai, China.
authors.forename: Xian-Xian
authors.initials: XX
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Changhai Hospital, Shanghai, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Cardiology, Changhai Hospital, Shanghai, China.
authors.forename: Yong-Wen
authors.initials: YW
authors.lastname: Qin
authors.affiliation: 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.
authors.forename: Qing
authors.initials: Q
authors.lastname: Jing
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites / Q000235:genetics; D016022:Case-Control Studies; D003327:Coronary Disease / Q000235:genetics / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology*; D055785:Gene Knockdown Techniques; D006609:High Mobility Group Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050986:YY1 Transcription Factor / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C486329:Hbp1 protein, mouse; D006609:High Mobility Group Proteins; D008077:Lipoproteins, LDL; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse; C099252:oxidized low density lipoprotein; C533424:Hdac2 protein, mouse; C498618:Hdac5 protein, mouse; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases
keywords: Atherogenesis; Foam cell formation; HBP1; MicroRNA; YY1