Targeting choroidal vascular dysfunction via inhibition of circRNA-FoxO1 for prevention and management of myopic pathology
Targeting choroidal vascular dysfunction via inhibition of circRNA-FoxO1 for prevention and management of myopic pathology
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DOI：
10.1016/j.ymthe.2021.02.025
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发表时间：
2021-07-07
影响因子：
12.4
通讯作者：
Lu, Yi
中科院分区：
文献类型：
--
作者：
Li, Dan;Liu, Chang;Lu, Yi
近视由于其高患病率已成为一个全球性的公共卫生问题。虽然近视的病因已逐渐被认识，但其发病机制仍不清楚。脉络膜血管功能障碍被认为是近视眼的一种严重的威胁视力的并发症。环状RNA（circRNAs）是许多生物学过程和人类疾病的重要调控因子。在这项研究中，我们研究了circRNA在近视眼脉络膜血管功能障碍中的作用。近视眼脉络膜中circFoxO 1的水平显著上调。circFoxO 1沉默在体外抑制脉络膜内皮细胞活力、增殖、迁移和管形成，并在体内和离体减轻脉络膜血管功能障碍。circFoxO 1沉默延缓了近视的进展，表现为细胞外基质重塑减少，屈光不正和眼轴延长改善。在机制上，circFoxO 1作为miR-145的海绵，隔离并抑制miR-145的活性，从而诱导VEGFA或ANGPT 2表达。miR-145可以模拟circFoxO 1沉默对脉络膜内皮表型的影响。总之，通过调节circFoxO 1水平来干预脉络膜血管功能障碍是预防和治疗近视的一种潜在策略。
Myopia has become a global public health problem due to high prevalence. Although the etiological factors of myopia have been gradually recognized, the underlying mechanism remains largely elusive. Choroidal vascular dysfunction is recognized as a critical vision-threatening complication in myopia. Circular RNAs (circRNAs) are shown as the critical regulators in many biological processes and human diseases. In this study, we investigated the role of circRNAs in choroidal vascular dysfunction in myopia. The level of circFoxO1 was significantly upregulated in myopic choroid. circFoxO1 silencing suppressed choroidal endothelial cell viability, proliferation, migration, and tube formation in vitro and alleviated choroidal vascular dysfunction in vivo and ex vivo. circFoxO1 silencing retarded the progression of myopia as shown by reduced extracellular matrix remodeling and improved refractive error and axial elongation. Mechanistically, circFoxO1 acted as the sponge of miR-145 to sequester and inhibit miR-145 activity, thereby inducing VEGFA or ANGPT2 expression. miR-145 could mimic the effects of circFoxO1 silencing on choroidal endothelial phenotypes. Collectively, intervention of choroidal vascular dysfunction via regulating circFoxO1 level is a potential strategy for the prevention and management of myopia.