The HAT Inhibitor ISOX-DUAL Diminishes Ischemic Areas in a Mouse Model of Oxygen-Induced Retinopathy

Abstract

Retinal ischemic disease results in significant visual impairment due to the development of fragile and disorganized, pathologically running blood vessels in the eye. Currently, the mainstay treatment for this disease is the intravitreal administration of anti-VEGF drugs targeting vascular endothelial growth factor (VEGF), which induces angiogenesis. However, current anti-VEGF drugs do not diminish the ischemic areas that lead to angiogenesis, making fundamental treatment challenging. Since retinopathy is an acquired disease caused by hypoxic stimulation from ischemia, we paid particular attention to histone acetylases. We conducted a drug screening experiment using a mouse model of oxygen-induced retinopathy (OIR), which replicates retinal ischemic disease, through the intraperitoneal administration of 17 distinct inhibitors targeting histone acetyltransferases (HAT). The results indicated that, among the 17 inhibitors, only ISOX-DUAL decreased neovascularization and ischemic regions. Furthermore, microarray analysis was conducted on the drug-treated samples to refine genes altered by the administration of ISOX-DUAL. There were 21 genes associated with angiogenesis, including Angpt2, Hmox1, Edn1, and Serpine1, exhibited upregulation in OIR mice and downregulation following treatment with ISOX-DUAL. Furthermore, STRING analysis confirmed that the aforementioned four genes are downstream factors of hypoxia-inducible factors and are assumed to be important factors in retinal ischemic diseases.