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Published on: November 17, 2017
Elevated microRNA-155 promotes foam cell formation by targeting HBP1 in atherogenesis
Fu-Ju Tian1, Li-Na An2, Guo-Kun Wang1
1The 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.
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.
Insights
MicroRNA-155 (miR-155) promotes macrophage foam cell formation in atherosclerosis by targeting HBP1. Inhibiting miR-155 reduces lipid accumulation and atherosclerotic plaques, suggesting miR-155 as a therapeutic target.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Inflammation Research
Background:
- MicroRNAs (miRNAs) are crucial regulators of macrophage inflammatory responses.
- The specific role of miRNAs in macrophage-derived foam cell formation and atherosclerosis remains largely undefined.
- Understanding these mechanisms is vital for developing novel therapeutic strategies.
Purpose of the Study:
- To elucidate the function of miRNAs in macrophage-derived foam cell formation.
- To investigate the role of miRNAs in the development of atherosclerosis.
- To identify novel regulatory pathways involved in these processes.
Main Methods:
- Quantitative reverse transcription-PCR (qRT-PCR) to measure miR-155 expression.
- Oxidized low-density lipoprotein (oxLDL) stimulation of macrophages.
- Overexpression and knockdown experiments for miR-155 and HBP1.
- Bioinformatics analysis to identify transcription factor binding sites.
- In vivo studies using ApoE(-/-) mice and antagomiR-155 treatment.
- Analysis of human CD14(+) monocytes from coronary heart disease patients.
Main Results:
- miR-155 expression is significantly upregulated in plasma and macrophages of atherosclerosis-prone mice and in monocytes from patients with coronary heart disease.
- Oxidized low-density lipoprotein (oxLDL) induces miR-155 expression and release, promoting lipid uptake and reactive oxygen species (ROS) production in macrophages.
- HMG box-transcription protein 1 (HBP1) is identified as a direct target of miR-155; its knockdown enhances, while overexpression represses, oxLDL-induced effects.
- The transcription factor Yin Yang 1 (YY1) complex negatively regulates miR-155 expression, suppressing foam cell formation.
- Systemic inhibition of miR-155 reduces lipid loading in macrophages and attenuates atherosclerotic plaques in vivo.
Conclusions:
- A novel regulatory pathway involving YY1/HDACs/miR-155/HBP1 is identified in macrophage foam cell formation during early atherogenesis.
- miR-155 plays a critical role in promoting macrophage-derived foam cell formation and atherosclerotic development.
- miR-155 emerges as a promising therapeutic target for atherosclerosis.
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