Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China; University of Chinese Academy of Sciences, No.19 A Yuquan Road, Beijing 100049, China.
Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19 A Yuquan Road, Beijing 100049, China.
Pharmacol Res. 2021 May;167:105562. doi: 10.1016/j.phrs.2021.105562. Epub 2021 Mar 16.
PCSK9 has emerged as a promising new therapeutic target for hyperlipidemia. The efficacy of PCSK9 siRNA in clinic trials clues the feasibility of exploring more PCSK9 inhibitors based on genetic inhibition in the treatment of hyperlipidemia. MicroRNAs (miRNAs) as a class of endogenous non-coding small RNAs can regulate genes at transcriptional and/or translational level. Here, we screened miRNAs from the prediction of TargetScan database with possible inhibitory activities in PCSK9 protein level via AlphaLISA and Western blotting, in which miR-552-3p was selected out for its strongest inhibitory effect. MiR-552-3p could bind to the 3' untranslated region (3'-UTR) of PCSK9 to inhibit translation and interact with the promoter of PCSK9 to suppress transcription. Further in vitro and in vivo experiments proved the effects of miR-552-3p on PCSK9 and downstream effectors: it could increase LDLR protein level, promote LDL-C uptake in HepG2 cells and lower serum LDL-C in high fat diet (HFD)-fed mice. In conclusion, our findings firstly identified miR-552-3p as a new PCSK9 inhibitor with the dual-inhibition mechanism, which suggested the possible application of miR-552-3p in the treatment of hyperlipidemia.
PCSK9 已成为治疗高血脂症的一种很有前途的新靶点。PCSK9 siRNA 在临床试验中的疗效表明，基于遗传抑制探索更多 PCSK9 抑制剂治疗高血脂症是可行的。microRNAs（miRNAs）作为一类内源性非编码小分子 RNA，可以在转录和/或翻译水平上调节基因。在这里，我们通过 AlphaLISA 和 Western blot 从 TargetScan 数据库的预测中筛选出对 PCSK9 蛋白水平具有潜在抑制活性的 miRNAs，其中 miR-552-3p 因其最强的抑制作用而被选中。miR-552-3p 可以与 PCSK9 的 3'非翻译区（3'-UTR）结合，抑制翻译，并与 PCSK9 的启动子相互作用，抑制转录。进一步的体外和体内实验证明了 miR-552-3p 对 PCSK9 和下游效应物的作用：它可以增加 LDLR 蛋白水平，促进 HepG2 细胞中 LDL-C 的摄取，并降低高脂肪饮食（HFD）喂养小鼠的血清 LDL-C。总之，我们的研究结果首次确定 miR-552-3p 是一种具有双重抑制机制的新型 PCSK9 抑制剂，这表明 miR-552-3p 可能在治疗高血脂症方面有应用前景。
