MicroRNA-181a-5p and microRNA-181a-3p cooperatively restrict vascular inflammation and atherosclerosis
MicroRNA-181a-5p and microRNA-181a-3p cooperatively restrict vascular inflammation and atherosclerosis
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MicroRNA-181a-5p和microRNA-181a-3p协同抑制血管炎症和动脉粥样硬化
DOI：
10.1038/s41419-019-1599-9
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发表时间：
2019-05-07
影响因子：
9
通讯作者：
Shang, Jinyan
中科院分区：
文献类型：
--
作者：
Su, Yingxue;Yuan, Jiani;Shang, Jinyan
MicroRNA是基因表达的重要转录后调节因子，参与多种疾病和细胞过程。miR-181 a在冠心病患者中表达降低，但其在动脉粥样硬化形成中的作用及机制尚不清楚。本研究旨在确定miR-181 a-5 p及其乘客链miR-181 a-3 p在血管炎症和动脉粥样硬化形成中的作用。我们发现miR-181 a-5 p和miR-181 a-3 p的水平在高脂血症时apoE−/−小鼠的主动脉斑块和血浆中以及冠状动脉疾病患者的血浆中均降低。拯救miR-181 a-5 p和miR-181 a-3 p可显著延缓apoE−/−小鼠动脉粥样硬化斑块的形成miR-181 a-5 p和miR-181 a-3 p对脂质代谢无影响，但可降低促炎基因表达，减少巨噬细胞、白细胞和T细胞向病变的浸润。此外，功能获得和功能丧失实验表明，miR-181 a-5 p和miR-181 a-3 p抑制HUVEC中粘附分子的表达和单核细胞-内皮细胞相互作用。miR-181 a-5 p和miR-181 a-3 p协同抑制内皮细胞炎症反应。miR-181 a-5 p和miR-181 a-3 p分别通过靶向TAB 2和NEMO阻断NF-κB信号通路来防止内皮细胞活化。总之，这些发现表明miR-181 a-5 p和miR-181 a-3 p都是抗动脉粥样硬化的miRNA。miR-181 a-5 p和miR-181 a-3 p模拟物分别通过靶向TAB 2和NEMO阻断NF-κB活化和血管炎症来延缓动脉粥样硬化进展。因此，miR-181 a-5 p和miR-181 a-3 p的恢复可能代表了一种新的治疗方法来管理动脉粥样硬化。
MicroRNAs have emerged as important post-transcriptional regulators of gene expression and are involved in diverse diseases and cellular process. Decreased expression of miR-181a has been observed in the patients with coronary artery disease, but its function and mechanism in atherogenesis is not clear. This study was designed to determine the roles of miR-181a-5p, as well as its passenger strand, miR-181a-3p, in vascular inflammation and atherogenesis. We found that the levels of both miR-181a-5p and miR-181a-3p are decreased in the aorta plaque and plasma of apoE−/−mice in response to hyperlipidemia and in the plasma of patients with coronary artery disease. Rescue of miR-181a-5p and miR-181a-3p significantly retards atherosclerotic plaque formation in apoE−/−mice. MiR-181a-5p and miR-181a-3p have no effect on lipid metabolism but decrease proinflammatory gene expression and the infiltration of macrophage, leukocyte and T cell into the lesions. In addition, gain-of-function and loss-of-function experiments show that miR-181a-5p and miR-181a-3p inhibit adhesion molecule expression in HUVECs and monocytes-endothelial cell interaction. MiR-181a-5p and miR-181a-3p cooperatively receded endothelium inflammation compared with single miRNA strand. Mechanistically, miR-181a-5p and miR-181a-3p prevent endothelial cell activation through blockade of NF-κB signaling pathway by targeting TAB2 and NEMO, respectively. In conclusion, these findings suggest that miR-181a-5p and miR-181a-3p are both antiatherogenic miRNAs. MiR-181a-5p and miR-181a-3p mimetics retard atherosclerosis progression through blocking NF-κB activation and vascular inflammation by targeting TAB2 and NEMO, respectively. Therefore, restoration of miR-181a-5p and miR-181a-3p may represent a novel therapeutic approach to manage atherosclerosis.