Wu Jiali, Chen Jieqiong, Hu Jing, Yao Mudi, Zhang Min, Wan Xiaoling, Jia Huixun, Wang Fenghua, Sun Xiaodong
Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Department of Ophthalmology, Shanghai General Hospital, National Clinical Research Center for Ophthalmic Diseases, Shanghai, China.
Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Department of Ophthalmology, Shanghai General Hospital, National Clinical Research Center for Ophthalmic Diseases, Shanghai, China; Department of Ophthalmology, Shanghai General Hospital, Shanghai Key Laboratory of Fundus Diseases, Shanghai, China; Department of Ophthalmology, Shanghai General Hospital, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China.
Transl Res. 2023 Jun;256:41-55. doi: 10.1016/j.trsl.2023.01.003. Epub 2023 Jan 20.
Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness in the elderly population. Neovascular AMD is the late stage, characterized by choroidal neovascularization (CNV). Non-coding RNAs have been implicated in CNV; however, the role of circular RNAs (circRNAs) has not yet been elucidated. Herein, we comprehensively investigated circRNA profiles in laser-induced CNV mouse models and patient specimens. A novel circRNA, circRNA Uxs1, was identified, and its function in CNV regulation was investigated in the present study. CircRNA Uxs1 was consistently upregulated in CNV patient specimens and CNV mouse models. Knockdown of circRNA Uxs1 interrupted the tube formation, migration, and proliferation of endothelial cells in vitro. Silencing circRNA Uxs1 in vivo alleviated neovascularization formation, as shown by the decreased size of laser spots. Mechanistically, circRNA Uxs1 functioned by binding to miR-335-5p, which further upregulated the expression of placental growth factor (PGF) gene and activated the mammalian target of rapamycin/p70 S6 Kinase (mTOR/p70 S6k) pathway. By subretinal injections of adeno-associated virus (AAV), we demonstrated the anti-angiogenic function of circRNA Uxs1 knockdown in vivo. In conclusion, circRNA Uxs1 promoted CNV by sponging miR-335-5p, which stimulated PGF expression and subsequently activated the mTOR/p70 S6k pathway. Therefore, circRNA Uxs1 may serve as a promising therapeutic target for CNV.
年龄相关性黄斑变性（AMD）是老年人群不可逆性失明的主要原因之一。新生血管性AMD是晚期阶段，其特征为脉络膜新生血管形成（CNV）。非编码RNA与CNV有关；然而，环状RNA（circRNA）的作用尚未阐明。在此，我们全面研究了激光诱导的CNV小鼠模型和患者标本中的circRNA谱。本研究鉴定了一种新型circRNA，即circRNA Uxs1，并研究了其在CNV调控中的作用。circRNA Uxs1在CNV患者标本和CNV小鼠模型中持续上调。敲低circRNA Uxs1可在体外中断内皮细胞的管形成、迁移和增殖。体内沉默circRNA Uxs1可减轻新生血管形成，如激光光斑大小减小所示。机制上，circRNA Uxs1通过与miR-335-5p结合发挥作用，进而上调胎盘生长因子（PGF）基因的表达并激活雷帕霉素哺乳动物靶标/p70 S6激酶（mTOR/p70 S6k）通路。通过视网膜下注射腺相关病毒（AAV），我们在体内证明了敲低circRNA Uxs1的抗血管生成功能。总之，circRNA Uxs1通过海绵吸附miR-335-5p促进CNV，miR-335-5p刺激PGF表达并随后激活mTOR/p70 S6k通路。因此，circRNA Uxs1可能成为CNV的一个有前景的治疗靶点。
