Atorvastatin Alleviates Age-Related Macular Degeneration via AIM2-Regulated Pyroptosis.

Abstract

The underlying causes of age-related macular degeneration (AMD) remain elusive and treatment options of it are limited, while atorvastatin (AT) is expected to improve AMD. Our study sought to uncover the specific mechanisms that initiate pyroptosis in AMD and elucidate whether AT ameliorates Aβ1-40-induced retinal damage by inhibiting pyroptosis. An animal model of AMD was triggered by Aβ1-40, and the therapeutic efficacy of AT was evaluated by hematoxylin and eosin staining (H&E), Optical Coherence Tomography (OCT), Electroretinogram (ERG) and other methods. Utilizing network pharmacology in conjunction with transcriptomics, we identified potential therapeutic pathways. we employed Western blotting (WB) and quantitative real-time PCR (qPCR) methodologies to evaluate the levels of pyroptosis. In vitro system of retinal pigment epithelium (RPE) cells injury was caused by Aβ1-40 and subsequently treated with AT or JC2-11. The extent of pyroptosis was quantified using enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining and WB. Cell morphological changes were examined using light microscopy and scanning electron microscopy. Network pharmacology and transcriptomics identified AIM2/Caspase-1/GSDMD as the key pathway. AT improved the retinal morphological and functional damage caused by Aβ1-40, and decreased the production of AIM2, Asc, Caspase-1, GSDMD-N, Cleaved Caspase-1 and cytokines to exert an anti-inflammatory effect. In addition, AT improved the ruptured membrane of RPE cells caused by Aβ1-40. The use of JC2-11 further demonstrated that AT inhibits pyroptosis of RPE via AIM2/Caspase-1/GSDMD pathway activated by Aβ1-40. These discoveries illuminate the retinal conservation role of AT by effectively hindering the progression of pyroptosis.