Abstract
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.
Abbreviations:
actD (actinomycin D), AMD (age-related macular degeneration), AAV (adeno-associated virus), CCK-8 (Cell Counting Kit-8), CNV (choroidal neovascularization), circRNAs (circular RNAs), EdU (5-ethynyl-2-deoxyuridine), FFA (fluorescein fundus angiography), HIF-1α (hypoxia-inducible factor-1 alpha), HUVECs (human umbilical vein endothelial cells), KEGG (Kyoto Encyclopedia of Genes and Genomes), lncRNAs (long non-coding RNAs), miRNAs (microRNAs), mTOR/p70 S6k (mammalian target of rapamycin/p70 S6 kinase), nAMD (neovascular AMD), OCT (optical coherent tomography), PGF (placental growth factor), RAPA (rapamycin), RNase (ribonuclease), RPE (retinal pigmented epithelium), SD (standard deviation), siRNAs (small interfering RNAs), UTR (untranslated region), WT (wild-type), VEGD (vascular endothelial growth factor)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: January 20, 2023
Accepted:
January 3,
2023
Received in revised form:
December 17,
2022
Received:
September 14,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Elsevier Inc. All rights reserved.
