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MiR-181b Antagonizes Atherosclerotic Plaque Vulnerability Through Modulating Macrophage Polarization by Directly Targeting Notch1

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Abstract

Atherosclerotic plaque vulnerability is the major cause for acute stroke and could be regulated by macrophage polarization. MicroRNA-181b (miR-181b) was involved in macrophage differential. Here, we explore whether miR-181b could regulate atherosclerotic plaque vulnerability by modulating macrophage polarization and the underline mechanisms. In acute stroke patients with atherosclerotic plaque, we found that the serum level of miR-181b was decreased. Eight-week apolipoprotein E knockout (ApoE−/−) mice were randomly divided into three groups (N = 10): mice fed with normal saline (Ctrl), mice fed with high-fat diet, and tail vein injection with miRNA agomir negative control (AG-NC)/miR-181b agomir (181b-AG, a synthetic miR-181b agonist). We found that the serum level of miR-181b in AG-NC group was lower than that in Ctrl group. Moreover, 181b-AG could upregulate miR-181b expression, reduce artery burden and attenuate atherosclerotic plaque vulnerability by modulating macrophage polarization. In RAW264.7 cells treated with oxidized low-density lipoprotein (ox-LDL), we found miR-181b could reverse the function of ox-LDL on M1/M2 markers at both mRNA and protein levels. Furthermore, by employing luciferase reporter assay, we found that Notch1 was a direct target of miR-181b and could be regulated by miR-181b in vivo and in vitro. Finally, inhibition of Notch1 could abolish the function of downregulating miR-181b on increasing M2 phenotype macrophages. Our study demonstrates that administration of miR-181b could reduce atherosclerotic plaque vulnerability partially through modulating macrophage phenotype by directly targeting Notch1.

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Acknowledgments

The authors thank the support of the National Natural Science Foundation of China (Grants 81571119 and 81371311 to BH, 81301002 to YPX, 81301001 to MDW, 81400969 to QWH, 81400970 to ML, 31571039 to LQZ), National Research Foundation for the Doctoral Program of Higher Education of China (Grant 20120142110068 to BH), New Century Excellent Talents in University (Grant NCET-10-0406 to BH), Top-Notch Young Talents Program of China of 2014, Academic Frontier Youth Team of HUST to LQZ, and Program for Changjiang Scholars and Innovative Research Team in University (No. IRT13016) to JGC.

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Authors and Affiliations

  1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Tian-Hui An, Quan-Wei He, Yuan-Peng Xia, Sheng-Cai Chen, Suraj Baral, Ling Mao, Hui-Juan Jin, Ya-Nan Li, Meng-Die Wang & Bo Hu

  2. The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China

    Jian-Guo Chen & Ling-Qiang Zhu

  3. Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Ling-Qiang Zhu

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  1. Tian-Hui An
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Correspondence to Ling-Qiang Zhu or Bo Hu.

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Tian-Hui An, Quan-Wei He, and Yuan-Peng Xia contributed equally to this work.

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An, TH., He, QW., Xia, YP. et al. MiR-181b Antagonizes Atherosclerotic Plaque Vulnerability Through Modulating Macrophage Polarization by Directly Targeting Notch1. Mol Neurobiol 54, 6329–6341 (2017). https://doi.org/10.1007/s12035-016-0163-1

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  • DOI: https://doi.org/10.1007/s12035-016-0163-1

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