Scleral hypoxia is a target for myopia control
Scleral hypoxia is a target for myopia control
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巩膜缺氧是控制近视的目标
DOI：
10.1073/pnas.1721443115
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发表时间：
2018-07-24
影响因子：
11.1
通讯作者：
Zhou, Xiangtian
中科院分区：
文献类型：
--
作者：
Wu, Hao;Chen, Wei;Zhou, Xiangtian
近视是导致视力损害的主要原因。近视眼的特征是巩膜细胞外基质（ECM）重塑，但近视眼巩膜ECM重塑的启动子和信号通路尚不清楚。在本研究中，我们发现缺氧诱导因子-1 α（HIF-1α）信号通过肌成纤维细胞转分化促进近视。此外，抗缺氧治疗阻止了HIF-1α相关分子的变化，从而抑制了近视的进展。我们的研究结果明确了缺氧在巩膜ECM重塑和近视发展中的重要性。对近视眼巩膜缺氧的识别不仅为理解近视发展的机制提供了概念，而且为控制人类近视进展提供了可行的治疗方法。在世界范围内，近视是视力损害的主要原因。它是由于眼轴的不适当延伸以及伴随的由细胞外基质（ECM）重塑引起的巩膜强度和厚度的下降。然而，在近视眼中诱导巩膜ECM重塑的启动子和信号通路的身份是未知的。在这里，我们使用单细胞RNA测序来识别近视发展过程中巩膜中激活的途径。我们发现，缺氧信号，eIF 2信号，和mTOR信号通路被激活，在小鼠近视巩膜。与小鼠近视模型中缺氧通路的作用一致，来自全基因组关联研究和连锁分析的近三分之一的人类近视风险基因与缺氧诱导因子-1 α（HIF-1α）信号通路中的基因相互作用。此外，实验性近视选择性地诱导小鼠和豚鼠近视巩膜中的HIF-1α上调。此外，低氧暴露（5%O2）促进肌成纤维细胞转分化与下调人巩膜成纤维细胞中的I型胶原。重要的是，抗缺氧药物红景天苷和芒柄花素下调HIF-1α表达以及eIF 2 α和mTOR的磷酸化水平，减缓实验性近视进展，而不影响豚鼠正常的眼球生长。此外，eIF 2 α磷酸化抑制抑制实验性近视，而mTOR磷酸化诱导正常小鼠近视。总的来说，这些发现确定了缺氧在巩膜ECM重塑和近视发展中的重要作用，提示了通过改善缺氧来控制近视的治疗方法。
Significance Myopia is the leading cause of visual impairment. Myopic eyes are characterized by scleral extracellular matrix (ECM) remodeling, but the initiators and signaling pathways underlying scleral ECM remodeling in myopia are unknown. In the present study, we found that hypoxia-inducible factor-1α (HIF-1α) signaling promoted myopia through myofibroblast transdifferentiation. Furthermore, antihypoxic treatments prevented the HIF-1α–associated molecular changes, thus suppressing myopia progression. Our findings defined the importance of hypoxia in scleral ECM remodeling and myopia development. The identification of the scleral hypoxia in myopia not only provides a concept for understanding the mechanisms of myopia development but also suggests viable therapeutic approach to control myopia progression in humans. 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.