miR-27a regulates vascular remodeling by targeting endothelial cells' apoptosis and interaction with vascular smooth muscle cells in aortic dissection
miR-27a regulates vascular remodeling by targeting endothelial cells' apoptosis and interaction with vascular smooth muscle cells in aortic dissection
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miR-27a通过靶向内皮细胞凋亡以及与主动脉夹层血管平滑肌细胞的相互作用来调节血管重塑
DOI：
10.7150/thno.35737
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Jing, Zaiping
中科院分区：
文献类型：
--
作者：
Sun, Yudong;Xiao, Yu;Jing, Zaiping
理论基础：主动脉夹层(AD)是由主动脉壁细胞功能紊乱引起的，这在很大程度上归因于血管重构。由于我们对内皮细胞(ECs)在AD发病机制中的作用了解不完全，AD的治疗策略仍然有限。本研究旨在明确miR-27A在AD中的调节作用，为AD的非侵入性治疗提供机制基础。方法：采集正常和AD患者的主动脉标本，检测miR-27A的表达。通过体外和体内实验，探讨miR-27A在内皮细胞中差异表达的生物学效应及其对AD的调节作用。结果：MIR-27A在AD患者血管内膜中的表达低于正常对照组。在EC中miR-27A的下调是由于Fas相关蛋白死亡结构域(FADD)的表达上调和凋亡通路的激活，从而导致内皮细胞的凋亡。共培养体系培养上清液中生长分化因子8(GDF8)表达增强，基质金属蛋白酶-20(MMP20)表达受抑，miR-27A下调后，EC可促进血管平滑肌细胞迁移。在用antagomir稳定击倒miR-27A的AD小鼠模型上，FADD增加和内皮细胞凋亡增加。Agomir上调miR-27A对AD有保护作用。结论：以内皮细胞凋亡为靶点的miR-27A激活剂可显著减少AD的发生，为AD的治疗提供了新的策略。
Rationale: Aortic dissection (AD) is caused by functional disorder of cells in the aortic wall, which is largely attributed to vascular remodeling. Therapeutic strategies for AD remain limited due to our incomplete understanding of the role of endothelial cells (ECs) in AD pathogenesis. This study aimed to identify the regulatory role of miR-27a in AD and provide a mechanistic basis for a non-invasive treatment of AD. Methods: We harvested aortas from normal and AD patients to explore the expression of miR-27a. In vitro and in vivo assays were preformed to explore the biological effects of differential expression of miR-27a in ECs and its regulatory effect on AD. Results: MiR-27a was lower in intima of AD samples than in healthy individuals. Downregulation of miR-27a in EC was due to up-regulated expression of fas-associated protein with death domain (FADD) and the activation of apoptosis pathway, which led to apoptosis of ECs. Migration of vascular smooth muscle cells was promoted by EC after downregulation of miR-27a due to enhancement of growth/differentiation factor 8 (GDF8) and repression of matrix metalloproteinase-20 (MMP20) in the co-culture system supernatants. Increase in FADD and apoptosis of ECs to induce AD was shown using mouse models of AD in which miR-27a was stably knocked-down by antagomir. Up-regulation of miR-27a by agomir led to a protective effect on AD. Conclusion: Treatment with miR-27a activator that targets apoptosis of ECs strongly diminished occurrence of AD, providing a new strategy for this disease.