Department of Ophthalmology, The Affiliated Hospital of Guizhou Medical University, Guiyang 550002, China.
School of Clinical Medicine, Guizhou Medical University, Guiyang 550002, China.
Oxid Med Cell Longev. 2022 Jun 9;2022:1671438. doi: 10.1155/2022/1671438. eCollection 2022.
Increasing studies have identified the function of sirtuin-1 (SIRT1) in ocular diseases. Hence, this study is aimed at exploring the potential role of SIRT1 in choroidal neovascularization- (CNV-) induced age-related macular degeneration (AMD) development and the associated mechanism. Expression of SIRT1/SOX9/LCN2 in the hypoxic cells was determined, and their interactions were predicted by bioinformatics websites and followed by the verification by luciferase assay and chromatin immunoprecipitation (ChIP). Their effects on hypoxic cells concerning cell viability, apoptosis, migration, and angiogenesis were detected through gain- and loss-of-function assays. Besides, their effect was explored using the established CNV mouse models. Highly expressed LCN2, SOX9, and SIRT1 were observed in hypoxic cells. LCN2 was increased by SOX9 and SIRT1 deacetylated SOX9 to promote its nuclear translocation, which further inhibited the viability of human retinal pigment epithelial cells and promoted cell apoptosis and angiogenesis as well as CNV-induced AMD formation. The relieving role of LCN2 inhibition on CNV-induced AMD without toxicity for mice was also demonstrated by experiments. Overall, SIRT1 promoted the formation of CNV-induced AMD through SOX9 deacetylation-caused LCN2 upregulation, representing a promising target for CNV-induced AMD management.
越来越多的研究已经确定了沉默信息调节因子 1（SIRT1）在眼部疾病中的功能。因此，本研究旨在探讨 SIRT1 在脉络膜新生血管化（CNV）诱导的年龄相关性黄斑变性（AMD）发展中的潜在作用及其相关机制。确定了缺氧细胞中 SIRT1/SOX9/LCN2 的表达，并通过生物信息学网站预测它们之间的相互作用，然后通过荧光素酶测定和染色质免疫沉淀（ChIP）进行验证。通过功能获得和功能丧失实验检测它们对缺氧细胞活力、凋亡、迁移和血管生成的影响。此外，还利用建立的 CNV 小鼠模型探索了它们的作用。在缺氧细胞中观察到高表达的 LCN2、SOX9 和 SIRT1。SOX9 增加了 LCN2，SIRT1 去乙酰化 SOX9 以促进其核易位，从而进一步抑制人视网膜色素上皮细胞的活力，促进细胞凋亡和血管生成以及 CNV 诱导的 AMD 形成。实验还证明了 LCN2 抑制对 CNV 诱导的 AMD 的缓解作用而对小鼠没有毒性。总的来说，SIRT1 通过 SOX9 去乙酰化引起的 LCN2 上调促进了 CNV 诱导的 AMD 的形成，这为 CNV 诱导的 AMD 管理提供了一个有前途的靶点。
