CircTHADA regulates endothelial cell pyroptosis in diabetic retinopathy through miR-494-3p/CASP1/GSDMD-N/IL-1β pathway.

Abstract

Our study aimed to elucidate the mechanism by which circTHADA competitively adsorbs miR-494-3p to regulate CASP1-mediated endothelial cell (EC) pyroptosis in diabetic retinopathy (DR). To be specific, we used high glucose (HG)-induced human retinal microvascular endothelial cells (HRMECs) as DR cell models and streptozotocin (STZ)-treated mice as DR mouse models. The expression levels of circTHADA, miR-494-3p, CASP1, NLRP3, GSDMD-N and IL-1β were detected and flow cytrometry was applied to measure cell pyroptosis rate and dual luciferase reporter assays were utilized to determine the direct binding sites. As a result, exacerbated EC pyroptosis in DR was detected in DR cell and mouse models. Based on DE-circRNA profiles by microarray and experimental verification, circTHADA was filtered and identified to regulate CASP1-mediated EC pyroptosis. miR-494-3p was then proven to be involved in circTHADA-mediated ceRNA network by bioinformatics analysis and experimental verification. Further gain- and loss-of-function experiments and rescue experiments revealed the function of the circTHADA/miR-494-3p/CASP1 axis in pyroptosis.