Sirtuin 1 Induces Choroidal Neovascularization and Triggers Age-Related Macular Degeneration by Promoting LCN2 through SOX9 Deacetylation

Abstract

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 in vitro effects on hypoxic cells concerning cell viability, apoptosis, migration, and angiogenesis were detected through gain- and loss-of-function assays. Besides, their in vivo 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 in vivo 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.