Tan Lili, Meng Liang, Shi Xiaojing, Yu Bo
Department of Cardiology, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, Liaoning, People's Republic of China.
Department of Cardiology, Central Hospital Affiliated to Shenyang Medical College, Shenyang, 110024, Liaoning, People's Republic of China.
Biotechnol Lett. 2017 Jul;39(7):967-976. doi: 10.1007/s10529-017-2337-y. Epub 2017 Apr 3.
To propose and verify a hypothesis that miR-17-5p knockdown may mitigate atherosclerotic lesions using atherosclerotic ApoE mice as serum microRNA-17-5p (miR-17-5p) is elevated in patients with atherosclerosis.
The level of miR-17-5p was higher while the level of very low density lipoprotein receptor (VLDLR), a predicted target of miR-17-5p, was lower in the peripheral blood lymphocytes (PBLs) of atherosclerosis patients as compared with control PBLs. ApoE mice fed with a high-cholesterol diet displayed marked atherosclerotic vascular lesions, which were ameliorated after treatment with antagomiR-17-5p. Moreover, the decreased VLDLR in atherosclerotic mice was partly restored when miR-17-5p was antagonized. Further, luciferase assay confirmed VLDLR as a direct target of miR-17-5p in vascular smooth muscle cells (VSMCs). In addition, the elevated expression of proprotein convertase subtilisin kexin 9 (PCSK9), a secreted protease that binds to and promotes VLDLR degradation, in the atherosclerotic mice was suppressed by antagomiR-17-5p.
A novel interaction between miR-17-5p and VLDLR is revealed and suggests that miR-17-5p may be a potential therapeutic target for AS.
鉴于动脉粥样硬化患者血清微小RNA-17-5p（miR-17-5p）水平升高，提出并验证miR-17-5p敲低可能减轻动脉粥样硬化病变的假说，以动脉粥样硬化ApoE小鼠为研究对象。
与对照外周血淋巴细胞（PBLs）相比，动脉粥样硬化患者PBLs中miR-17-5p水平较高，而miR-17-5p的预测靶标极低密度脂蛋白受体（VLDLR）水平较低。喂食高胆固醇饮食的ApoE小鼠出现明显的动脉粥样硬化血管病变，用抗miR-17-5p治疗后病变得到改善。此外，拮抗miR-17-5p时，动脉粥样硬化小鼠中降低的VLDLR部分恢复。进一步的荧光素酶测定证实VLDLR是血管平滑肌细胞（VSMC）中miR-17-5p的直接靶标。此外，抗miR-17-5p抑制了动脉粥样硬化小鼠中前蛋白转化酶枯草杆菌蛋白酶9（PCSK9）的表达升高，PCSK9是一种分泌型蛋白酶，可结合并促进VLDLR降解。
揭示了miR-17-5p与VLDLR之间的新型相互作用，提示miR-17-5p可能是动脉粥样硬化的潜在治疗靶点。
