Elevated microRNA-155 promotes foam cell formation by targeting HBP1 in atherogenesis

Fu Ju Tian, Li Na An, Guo Kun Wang, Jia Qi Zhu, Qing Li, Ying Ying Zhang, An Zeng, Jun Zou, Rong Fang Zhu, Xiao Shuai Han, Nan Shen, Huang Tian Yang, Xian Xian Zhao, Shuang Huang, Yong Wen Qin, Qing Jing

Research output: Contribution to journalArticlepeer-review

127 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)100-110
Number of pages11
JournalCardiovascular Research
Volume103
Issue number1
DOIs
StatePublished - Jul 1 2014

Keywords

  • Atherogenesis
  • Foam cell formation
  • HBP1
  • MicroRNA
  • YY1

ASJC Scopus subject areas

  • General Medicine

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