Scleral hypoxia is a target for myopia control
| Autor: | Hao Wu, Yinghui Xiong, Yang Hu, Jidong Lang, Fei Zhao, Jing Sun, Miaozhen Pan, Jianhuo Fang, Qingyi Zhou, Ran Ren, Zhonglou Zhou, Sen Zhang, Deng Wu, Nethrajeith Srinivasalu, Lili Deng, Peter S. Reinach, Jia Qu, Shumeng Luo, Lina Zhang, Xiangtian Zhou, Changqing Zeng, Wei Chen, Xiaomeng Pei, Li Ma, Geng Tian |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty genetic structures Eukaryotic Initiation Factor-2 Guinea Pigs Extracellular matrix Mice 03 medical and health sciences 0302 clinical medicine Internal medicine Myopia Animals Humans Medicine Eye Proteins Hypoxia PI3K/AKT/mTOR pathway Multidisciplinary business.industry TOR Serine-Threonine Kinases Transdifferentiation Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit eye diseases Extracellular Matrix Sclera Disease Models Animal 030104 developmental biology Endocrinology medicine.anatomical_structure PNAS Plus 030221 ophthalmology & optometry Phosphorylation sense organs Signal transduction medicine.symptom business Myofibroblast Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 115 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Worldwide, myopia is the leading cause of visual impairment. It results from inappropriate extension of the ocular axis and concomitant declines in scleral strength and thickness caused by extracellular matrix (ECM) remodeling. However, the identities of the initiators and signaling pathways that induce scleral ECM remodeling in myopia are unknown. Here, we used single-cell RNA-sequencing to identify pathways activated in the sclera during myopia development. We found that the hypoxia-signaling, the eIF2-signaling, and mTOR-signaling pathways were activated in murine myopic sclera. Consistent with the role of hypoxic pathways in mouse model of myopia, nearly one third of human myopia risk genes from the genome-wide association study and linkage analyses interact with genes in the hypoxia-inducible factor-1α (HIF-1α)–signaling pathway. Furthermore, experimental myopia selectively induced HIF-1α up-regulation in the myopic sclera of both mice and guinea pigs. Additionally, hypoxia exposure (5% O2) promoted myofibroblast transdifferentiation with down-regulation of type I collagen in human scleral fibroblasts. Importantly, the antihypoxia drugs salidroside and formononetin down-regulated HIF-1α expression as well as the phosphorylation levels of eIF2α and mTOR, slowing experimental myopia progression without affecting normal ocular growth in guinea pigs. Furthermore, eIF2α phosphorylation inhibition suppressed experimental myopia, whereas mTOR phosphorylation induced myopia in normal mice. Collectively, these findings defined an essential role of hypoxia in scleral ECM remodeling and myopia development, suggesting a therapeutic approach to control myopia by ameliorating hypoxia. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|