Amgen Biopharmaceutical Research and Development (Shanghai) Co., Ltd., Shanghai, China.
Department of Cardiometabolic Disorders, Amgen Research, Amgen Inc., Thousand Oaks, CA, USA.
J Lipid Res. 2020 Dec;61(12):1764-1775. doi: 10.1194/jlr.RA120001121. Epub 2020 Oct 2.
Of the known regulators of atherosclerosis, miRNAs have been demonstrated to play critical roles in lipoprotein homeostasis and plaque formation. Here, we generated a novel animal model of atherosclerosis by knocking in in C57BL/6 mice, as the W483X mutation in is considered the most common newly identified pathogenic mutation in Chinese familial hypercholesterolemia (FH) individuals. Using the new in vivo mouse model combined with a well-established atherosclerotic in vitro human cell model, we identified a novel atherosclerosis-related miRNA, miR-23a-3p, by microarray analysis of mouse aortic tissue specimens and human aortic endothelial cells (HAECs). miR-23a-3p was consistently downregulated in both models, which was confirmed by qPCR. Bioinformatics analysis and further validation experiments revealed that the TNFα-induced protein 3 () gene was the key target of miR-23a-3p. The miR-23a-3p-related functional pathways were then analyzed in HAECs. Collectively, the present results suggest that miR-23a-3p regulates inflammatory and apoptotic pathways in atherogenesis by targeting through the NF-κB and p38/MAPK signaling pathways.
在已知的动脉粥样硬化调节因子中，miRNA 被证明在脂蛋白稳态和斑块形成中发挥关键作用。在这里，我们通过在 C57BL/6 小鼠中敲入 ，创建了一种新的动脉粥样硬化动物模型，因为 中的 W483X 突变被认为是中国家族性高胆固醇血症（FH）个体中最常见的新发现的致病性突变。我们使用新的体内小鼠模型结合成熟的动脉粥样硬化体外人细胞模型，通过对小鼠主动脉组织标本和人主动脉内皮细胞（HAEC）的微阵列分析，鉴定出一种新的与动脉粥样硬化相关的 miRNA，miR-23a-3p。miR-23a-3p 在两种模型中均一致下调，这通过 qPCR 得到了证实。生物信息学分析和进一步的验证实验表明，TNFα 诱导蛋白 3（）基因是 miR-23a-3p 的关键靶基因。然后在 HAEC 中分析了与 miR-23a-3p 相关的功能途径。综上所述，这些结果表明，miR-23a-3p 通过 NF-κB 和 p38/MAPK 信号通路靶向 ，调节动脉粥样硬化形成中的炎症和凋亡途径。
