Wang Beiyun, Zhong Yuan, Huang Dong, Li Jingbo
Department of Gerontology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University 600 Yishan Road, Shanghai 200233, China.
Department of Cardiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University 600 Yishan Road, Shanghai 200233, China.
Am J Transl Res. 2016 Feb 15;8(2):606-14. eCollection 2016.
Macrophages play an essential and complicated role in the pathogenesis of atherosclerosis. However, the regulation of macrophage autophagy as well as it role in the development of atherosclerosis is unclear. MicroRNA-384-5p (miR-384-5p) is a new miRNA that attracted attention very recently, while its effects on Beclin-1 and cell autophagy has not been reported. Here, we studied macrophage autophagy in ApoE (-/-) mice suppled with high-fat diet (HFD), a mouse model for atherosclerosis (simplified as HFD mice). We analyzed the levels of Beclin-1 and the levels of miR-384-5p in the purified F4/80+ macrophages from mouse aorta. Prediction of the binding between miR-384-5p and 3'-UTR of Beclin-1 mRNA was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. We found that HFD mice developed atherosclerosis in 12 weeks, while the control ApoE (-/-) mice that had received normal diet (simplified as NOR mice) did not. Compared to NOR mice, HFD mice had significantly lower levels of macrophage autophagy, and significantly higher levels of macrophage death, resulting from decreases in Beclin-1. The decreases in Beclin-1 in macrophages were due to HFD-induced increases in miR-384-5p, which suppressed the translation of Bectlin-1 mRNA via 3'-UTR binding. Together, our study suggests that upregulation of miR-384-5p by HFD may impair the Beclin-1-mediated protection of macrophages through autophagy to accelerate the development of atherosclerosis.
巨噬细胞在动脉粥样硬化的发病机制中发挥着重要而复杂的作用。然而，巨噬细胞自噬的调节及其在动脉粥样硬化发展中的作用尚不清楚。微小RNA-384-5p（miR-384-5p）是一种最近才受到关注的新型微小RNA，但其对Beclin-1和细胞自噬的影响尚未见报道。在此，我们研究了高脂饮食（HFD）喂养的ApoE（-/-）小鼠（一种动脉粥样硬化小鼠模型，简称为HFD小鼠）中的巨噬细胞自噬。我们分析了从小鼠主动脉中纯化的F4/80+巨噬细胞中Beclin-1的水平和miR-384-5p的水平。通过生物信息学分析预测了miR-384-5p与Beclin-1 mRNA的3'-UTR之间的结合，并通过双荧光素酶报告基因检测进行了验证。我们发现HFD小鼠在12周时发生了动脉粥样硬化，而接受正常饮食的对照ApoE（-/-）小鼠（简称为NOR小鼠）则未发生动脉粥样硬化。与NOR小鼠相比，HFD小鼠的巨噬细胞自噬水平显著降低，巨噬细胞死亡水平显著升高，这是由于Beclin-1减少所致。巨噬细胞中Beclin-1的减少是由于HFD诱导的miR-384-5p增加，miR-384-5p通过3'-UTR结合抑制了Bectlin-1 mRNA的翻译。总之，我们的研究表明，HFD上调miR-384-5p可能会损害Beclin-1介导的通过自噬对巨噬细胞的保护作用，从而加速动脉粥样硬化的发展。
