MiR-181b Antagonizes Atherosclerotic Plaque Vulnerability Through Modulating Macrophage Polarization by Directly Targeting Notch1
MiR-181b Antagonizes Atherosclerotic Plaque Vulnerability Through Modulating Macrophage Polarization by Directly Targeting Notch1
复制标题
MiR-181b 通过直接靶向 Notch1 调节巨噬细胞极化来对抗动脉粥样硬化斑块脆弱性
DOI：
10.1007/s12035-016-0163-1
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发表时间：
2017-10-01
影响因子：
5.1
通讯作者：
Hu, Bo
中科院分区：
文献类型：
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作者：
An, Tian-Hui;He, Quan-Wei;Hu, Bo
动脉粥样硬化斑块易损性是急性卒中的主要原因，可通过巨噬细胞极化调节。MicroRNA-181b （miR-181b）参与巨噬细胞分化。在这里，我们探讨miR-181b是否可以通过调节巨噬细胞极化来调节动脉粥样硬化斑块易损及其潜在机制。在伴有动脉粥样硬化斑块的急性脑卒中患者中，我们发现血清中miR-181b水平降低。8周载脂蛋白E敲除（ApoE(-/-)）小鼠随机分为3组（N = 10）：生理盐水组（Ctrl）、高脂饮食组（高脂饮食组）、尾静脉注射miRNA agomir阴性对照(AG-NC)/miR-181b agomir （181b-AG，一种合成的miR-181b激动剂）。我们发现AG-NC组血清miR-181b水平低于对照组。此外，181b-AG可以通过调节巨噬细胞极化，上调miR-181b的表达，减轻动脉负荷，减轻动脉粥样硬化斑块易损。在氧化低密度脂蛋白（ox-LDL）处理的RAW264.7细胞中，我们发现miR-181b可以在mRNA和蛋白质水平上逆转ox-LDL对M1/M2标记物的功能。此外，通过荧光素酶报告基因实验，我们发现Notch1是miR-181b的直接靶点，在体内和体外均可受到miR-181b的调控。最后，抑制Notch1可以消除下调miR-181b增加M2表型巨噬细胞的功能。我们的研究表明，miR-181b可以通过直接靶向Notch1调节巨噬细胞表型，部分降低动脉粥样硬化斑块易感性。
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.