miR-30c inhibits angiogenesis by targeting delta-like ligand 4 in liver sinusoidal endothelial cell to attenuate liver fibrosis
miR-30c inhibits angiogenesis by targeting delta-like ligand 4 in liver sinusoidal endothelial cell to attenuate liver fibrosis
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DOI：
10.1096/fj.202002694r
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发表时间：
2021-05-01
期刊：
影响因子：
4.8
通讯作者：
Lu, Lungen
中科院分区：
文献类型：
--
作者：
Gu, Tianyi;Shen, Bo;Lu, Lungen
肝纤维化是慢性肝病期间肝功能障碍的常见特征，并且经常与血管生成相关，血管生成是从先前存在的脉管系统形成新血管的动态过程。 MicroRNA (miRNA) 作为基因表达的转录后调节因子，已被证明可以调节肝纤维化；然而，miRNA如何调节血管生成及其在纤维化中的机制尚不清楚。我们的目的是阐明 miR-30c 在减轻肝纤维化中的作用和机制。利用纤维化小鼠肝脏的 miRNA 分析，我们鉴定了差异调节的 miRNA，并发现 miR-30c 在四氯化碳治疗或胆管结扎的纤维化小鼠以及肝纤维化患者中异常表达并靶向内皮 δ 样配体 4 (DLL4)。使用 CCK-8、伤口愈合和基质胶管形成测定，我们发现 miR-30c 在体外通过靶向 DLL4 抑制肝窦内皮细胞 (LSEC) 增殖、迁移和血管生成能力。重要的是，基于纳米颗粒的 miR-30c 向 LSEC 的递送抑制了 DLL4/Notch 通路和血管生成，从而改善体内肝纤维化。总的来说，我们的研究结果证明了 miR-30c 通过调节 DLL4/Notch 信号传导和血管生成在肝纤维化中发挥保护作用。因此，miR-30c可能作为慢性肝病的潜在治疗方法。
Liver fibrosis is a common feature of liver dysfunction during chronic liver diseases and is frequently associated with angiogenesis, a dynamic process that forms new blood vessels from preexisting vasculature. MicroRNAs (miRNAs), which act as posttranscriptional regulators of gene expression, have been shown to regulate liver fibrosis; however, how miRNAs regulate angiogenesis and its mechanism in fibrosis are not well understood. We aimed to elucidate the role and mechanism of miR-30c in attenuating liver fibrosis. Using miRNA profiling of fibrotic murine livers, we identified differentially regulated miRNAs and discovered that miR-30c is aberrantly expressed and targets endothelial delta-like ligand 4 (DLL4) in either carbon tetrachloride-treated or bile duct ligated fibrotic mice, as well as in patients with liver fibrosis. Using CCK-8, wound healing and Matrigel tube formation assays, we found that miR-30c inhibited liver sinusoidal endothelial cell (LSEC) proliferation, migration, and angiogenesis capacity by targeting DLL4 in vitro. Importantly, nanoparticle-based delivery of miR-30c to LSECs inhibited the DLL4/Notch pathway and angiogenesis, thereby ameliorating liver fibrosis in vivo. Collectively, our findings demonstrate a protective role of miR-30c in liver fibrosis by regulating DLL4/Notch signaling and angiogenesis. Thus, miR-30c may serve as a potential treatment for chronic liver diseases.