HDAC3 mediates retinal endothelial cell metabolic reprogramming and angiogenesis

Area of Science:

• Ophthalmology
• Molecular Biology
• Cell Biology

Background:

• Pathological retinal neovascularization (NV) causes vision loss in diabetic retinopathy (DR) and retinopathy of prematurity.
• Retinal hypoxia is a key driver of NV, leading to uncontrolled and leaky blood vessel growth.
• Current therapies have limited effectiveness, highlighting the need for new therapeutic targets.

Purpose of the Study:

• To define the role of histone deacetylase 3 (HDAC3) in the pathogenesis of experimental NV.
• To investigate the molecular mechanisms by which HDAC3 influences retinal endothelial cell metabolism and angiogenesis.

Main Methods:

• Oxygen-induced retinopathy (OIR) model in mice to induce pathological NV.
• In vitro studies using cultured bovine retinal endothelial cells (REC) subjected to oxygen-glucose deprivation/reperfusion (OGD/R).
• Analysis of HDAC3 expression, cell migration, proteomic profiling, glycolysis, and mitochondrial morphology; treatment with HDAC3 inhibitor RGFP966 and mitochondrial fission inhibitor Mdivi-1.

Main Results:

• HDAC3 expression was increased in retinal vessels of OIR mice and human DR samples, and in REC after OGD/R.
• HDAC3 inhibition (RGFP966) or knockdown attenuated OGD/R-induced REC migration and angiogenesis.
• HDAC3 inhibition suppressed OGD/R-induced upregulation of hexokinase 2 (HK2), glycolysis, and mitochondrial fission.

Conclusions:

• HDAC3 plays a crucial role in pathological NV by promoting endothelial cell metabolic reprogramming toward glycolysis via mitochondrial fission and HK2 signaling.
• Targeting HDAC3 or its downstream metabolic pathways presents a promising therapeutic strategy for pathological NV.
• HDAC3 inhibition protects against OGD/R-induced metabolic changes and pathological angiogenesis in retinal endothelial cells.