State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 510060, Guangzhou, China.
Department of Pharmacology, Cardiac and Cerebrovascular Research Center, Zhongshan School of Medicine, 510080, Guangzhou, China.
Cell Death Dis. 2019 May 7;10(5):365. doi: 10.1038/s41419-019-1599-9.
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.
微小 RNA 已成为基因表达的重要转录后调控因子，参与多种疾病和细胞过程。在冠状动脉疾病患者中观察到 miR-181a 的表达降低，但它在动脉粥样硬化形成中的功能和机制尚不清楚。本研究旨在确定 miR-181a-5p 及其过客链 miR-181a-3p 在血管炎症和动脉粥样硬化形成中的作用。我们发现，在高脂血症反应中，apoE 小鼠的主动脉斑块和血浆以及冠状动脉疾病患者的血浆中，miR-181a-5p 和 miR-181a-3p 的水平均降低。miR-181a-5p 和 miR-181a-3p 的恢复显著延缓了 apoE 小鼠的动脉粥样硬化斑块形成。miR-181a-5p 和 miR-181a-3p 对脂质代谢没有影响，但可降低促炎基因表达以及巨噬细胞、白细胞和 T 细胞浸润病变。此外，功能获得和功能丧失实验表明，miR-181a-5p 和 miR-181a-3p 抑制 HUVECs 和单核细胞-内皮细胞相互作用中黏附分子的表达。miR-181a-5p 和 miR-181a-3p 与单条 miRNA 链相比，共同减轻内皮炎症。在机制上，miR-181a-5p 和 miR-181a-3p 通过分别靶向 TAB2 和 NEMO 阻断 NF-κB 信号通路来防止内皮细胞激活。总之，这些发现表明 miR-181a-5p 和 miR-181a-3p 都是抗动脉粥样硬化的 miRNA。miR-181a-5p 和 miR-181a-3p 模拟物通过分别靶向 TAB2 和 NEMO 阻断 NF-κB 激活和血管炎症，从而减缓动脉粥样硬化进展。因此，恢复 miR-181a-5p 和 miR-181a-3p 可能代表一种管理动脉粥样硬化的新治疗方法。
