Abstract 14633: Elevated microRNA-155 Promotes Foam Cell Formation by Targeting HBP1 in Atherogenesis
Aims: 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 level of miR-155 expression was increased significantly in both plasma and macrophages from atherosclerosis (ApoE-/-) mice. We identified that oxidized LDL (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. Further, 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. Electrophoretic mobility shift assay (EMSA) and Chromatin immunoprecipitation (ChIP) analysis 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, attenuated the level of pro-atherosclerotic factors in plasma, and reduced atherosclerotic plaques in ApoE-/- mice. Moreover, we observed that the level of miR-155 expression was upregulated 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.
- © 2013 by American Heart Association, Inc.