Qin Yan, Zheng Bin, Yang Gao-Shan, Yang Hao-Jie, Zhou Jing, Yang Zhan, Zhang Xin-Hua, Zhao Hong-Ye, Shi Jian-Hong, Wen Jin-Kun
Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang 050017, China; Department of Central Laboratory, Affiliated Hospital of Hebei University, Baoding 071000, China; Department of Life Science and Green Development, Hebei University, Baoding 071000, China.
Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, China Administration of Education, Hebei Medical University, Shijiazhuang 050017, China.
Mol Ther Nucleic Acids. 2020 Sep 4;21:492-511. doi: 10.1016/j.omtn.2020.06.015. Epub 2020 Jun 24.
Autophagy is associated with the cytoprotection of physiological processes against inflammation and oxidative stress. Salvia miltiorrhiza possesses cardiovascular protective actions and has powerful anti-oxidative and anti-inflammatory effects; however, whether and how Salvia miltiorrhiza-derived microRNAs (miRNAs) protect vascular smooth muscle cells (VSMCs) by inducing autophagy across species are unknown. We first screened and identified Sal-miR-58 from Salvia miltiorrhiza as a natural autophagy inducer. Synthetic Sal-miR-58 suppresses chronic angiotensin II (Ang II) infusion-induced abdominal aortic aneurysm (AAA) formation in mice, as well as induces autophagy in VSMCs and attenuates the inflammatory response elicited by Ang II in vivo and in vitro. Mechanistically, Sal-miR-58 downregulates Krüppel-like factor 3 (KLF3) expression through direct binding to the 3' UTR of KLF3, which in turn relieves KLF3 repression of E3 ubiquitin ligase neural precursor cell-expressed developmentally downregulated 4-like (NEDD4L) expression, whereas NEDD4L upregulation increases the ubiquitination and degradation of the platelet isoform of phosphofructokinase (PFKP), subsequently leading to a decrease in the activation of Akt/mammalian target of rapamycin (mTOR) signaling and facilitating VSMC autophagy induced by Sal-miR-58 in the context of chronic Ang II stimulation and aneurysm formation. Our results provide the first evidence that plant-derived Sal-miR-58 induces autophagy and attenuates inflammation in VSMCs through cross-species modulation of the KLF3/NEDD4L/PFKP regulatory pathway.
自噬与生理过程对炎症和氧化应激的细胞保护作用相关。丹参具有心血管保护作用，并具有强大的抗氧化和抗炎作用；然而，丹参衍生的微小RNA（miRNA）是否以及如何通过诱导自噬来保护跨物种的血管平滑肌细胞（VSMC）尚不清楚。我们首先从丹参中筛选并鉴定出Sal-miR-58作为一种天然的自噬诱导剂。合成的Sal-miR-58可抑制慢性血管紧张素II（Ang II）输注诱导的小鼠腹主动脉瘤（AAA）形成，同时在VSMC中诱导自噬，并减轻体内和体外Ang II引发的炎症反应。机制上，Sal-miR-58通过直接结合Krüppel样因子3（KLF3）的3'非翻译区（UTR）来下调KLF3的表达，这反过来又解除了KLF3对E3泛素连接酶神经前体细胞表达的发育下调4样蛋白（NEDD4L）表达的抑制，而NEDD4L的上调增加了磷酸果糖激酶血小板异构体（PFKP）的泛素化和降解，随后导致Akt/雷帕霉素哺乳动物靶标（mTOR）信号通路的激活减少，并在慢性Ang II刺激和动脉瘤形成的背景下促进Sal-miR-58诱导的VSMC自噬。我们的结果提供了首个证据，表明植物来源的Sal-miR-5通过KLF3/NEDD4L/PFKP调节途径的跨物种调节诱导VSMC自噬并减轻炎症。
