Abstract
Purpose :
To verify the therapeutic effect of histone deacetylase (HDAC) inhibitor tasquinimod on primary open-angle glaucoma (POAG) and clarify the mechanism of HDAC4 regulating trabecular meshwork cells (TMCs) PANopotosis.
Methods :
Microarray data (GSE27276) of TM tissue in POAG was downloaded from GEO database. CMap database was used to screen small molecule inhibitors for POAG. Aqueous humor and TM tissues were collected to assess expression levels of PANoptosis-related indicators (HMGB1, IL-1β, caspase-1,3,8, MLKL, NLRP3). H2O2-induced TMCs injury model was constructed. Injection of hypertonic saline into the episcleral vein was used to construct chronic ocular hypertension (COH) rat model. HDAC4 inhibitor tasquinimod was applied in vivo and in vitro to verify its therapeutic effects. PCR, Western blots and immunofluorescence were used to assess PANoptosis levels and extracellular matrix (ECM) remodeling. Co-immunoprecipitation (COIP) was performed to identify deacetylation position.
Results :
CMap analysis revealed that HDAC inhibitors possessed the potential to lower IOP. Microarray and immunohistochemistry results showed that HDAC4 was the key gene regulating TMCs injury. PANoptosis-related indicators were up-regulated in AH and TM tissues of POAG patients compared with that of controls. Tasquinimod and HDAC4 siRNA rescued H2O2-induced TMCs PANoptosis and ECM remodeling. CoIP suggested HDAC4 enhanced activity of caspase-1, 3, 8 by deacetylating lysine position 7, 11, 480. Tasquinimod intervention significantly lowered intraocular pressure of COH rats.
Conclusions :
Tasquinimod inhibited TMCs PANoptosis through deacetylation modification of caspases family to lower IOP in POAG.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.