Hsa-miRNA-23a-3p promotes atherogenesis in a novel mouse model of atherosclerosis
Hsa-miRNA-23a-3p promotes atherogenesis in a novel mouse model of atherosclerosis
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DOI：
10.1194/jlr.ra120001121
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发表时间：
2020-12-01
影响因子：
6.5
通讯作者：
Yin, Hong
中科院分区：
文献类型：
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作者：
Guo, Jiayan;Mei, Hanbing;Yin, Hong
在已知的动脉粥样硬化调节因子中，miRNAs已被证明在脂蛋白稳态和斑块形成中起关键作用。在此，我们通过敲入C57 BL/6小鼠中的LDLRW 483 X产生了一种新的动脉粥样硬化动物模型，因为LDLR中的W 483 X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突变。利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，我们通过微阵列分析小鼠主动脉组织标本和人主动脉内皮细胞（HAECs），鉴定了一种新的动脉粥样硬化相关miRNA，miR-23 a-3 p。miR-23 a-3 p在两种模型中一致下调，这通过qPCR证实。生物信息学分析和进一步的验证实验表明，TNF α诱导蛋白3（TNFAIP 3）基因是miR-23 a-3 p的关键靶点。然后在HAECs中分析miR-23 a-3 p相关的功能通路。总之，本研究结果表明，miR-23 a-3 p通过NF-κ B和p38/MAPK信号通路靶向TNFAIP 3调节动脉粥样硬化形成中的炎症和凋亡通路。
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 LDLRW483X in C57BL/6 mice, as the W483X mutation in LDLR 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 TNF alpha -induced protein 3 (TNFAIP3) 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 TNFAIP3 through the NF-kappa B and p38/MAPK signaling pathways.