Abstract
Purpose :
Clinical and animal studies suggest that inflammation plays a pivotal role in the pathogenesis of retinopathy of prematurity (ROP), diabetic retinopathy (DR), and age-related macular degeneration (AMD). Although developing anti-VEGF therapy to treat retinal neovascularization is successful, it also co-exists with significant adverse effects. Over the last decade, it has become clear that aconitate decarboxylase 1 (Acod1) and its metabolite itaconate play a critical role in the autocrine regulation of inflammation and immunity. This study aimed to investigate the function of Acod1/itaconate in pathological retinal neovascularization, since little is known about its involvement in proliferative retinopathies
Methods :
We used Oxygen-induced retinopathy (OIR) and human retinal microvascular endothelial cells (HRMVECs) as models to investigate the function of Acod1/itaconate in proliferative/ischemic retinopathies. We investigated the impact of Acod1 depletion on OIR-induced retinal endothelial cell proliferation, sprouting, and retinal neovascularization using Acod1+/+ and Acod1–/– as mice models. To reinforce our findings about the involvement of Acod1/itaconate in proliferative/ischemic retinopathies, Acod1+/+ and Acod1–/– mice were administered with intraperitoneal injections of 4-octyl itaconate (4-OI, @50 mg/Kg body weight) at P12 and P14. At P17 eyes were collected, retinas isolated and evaluated for retinal neovascularization, avascular area, and tip cell formation.
Results :
Retinal neovascularization or tuft formation was significantly upregulated in the ischemic retinas of Acod1–/– mice compared to Acod1+/+ mice. Intraperitoneal injections of 4-octyl itaconate significantly reduced ischemia-induced vascular leakage and edema in Acod1–/– mice and Acod1+/+ mice. We also observed a considerable reduction in endothelial cell sprouting and retinal neovascularization in 4-OI-treated mice retinas.
Conclusions :
Our results suggest that Acod1/itaconate pathway is a potential candidate as a therapeutic agent against retinal neovascularization.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.