Rank Order of Small Molecule Induced Hypoxiamimesis to Prevent Retinopathy of Prematurity

Abstract

Here we rank order small molecule inhibitors of hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) using severity of oxygen induced retinopathy (OIR) as an outcome measure. Dose response analyses in cell cultures of hepatoma (Hep3B), retinal Müller cells (MIO-M1) and primary retinal endothelial cells were conducted to evaluate potency by comparing dose to HIF-1,2 protein levels by western blotting. In vivo dose response was determined using the luciferase-transgene HIF reporter (luc-ODD). Each compound was placed in rank order by their ability to reduce neovascularization and capillary drop out in the OIR mouse model. An Epas1 KO confined to retinal Müller cells was used to determine whether successful protection by HIF stabilization requires HIF-2. Two candidate small molecules can prevent OIR by stabilizing HIF-1 to prevent oxygen induced growth attenuation and vascular obliteration. Müller cell HIF-2, the mediator of pathologic retinal angiogenesis, is not required for protection. The lack of dependence on Müller cell HIF-2 predicts that inhibition of HIF PHD will not drive pathological angiogenesis.

Clinical Potential of Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors in Treating Nonanemic Diseases

“…This indicated that apart from the up-mentioned hepatic angiogenic hepatokines, serine act as an alternative signaling molecular to achieve the remote regulation of liver to retinol and mediated roxadustat’s retinovascular protection effect ( Hoppe et al, 2016 ; Singh et al, 2019 ). Importantly, roxadustat demonstrated a weak induction effect on Müller cell HIF-2α, which is the main mediator of retina pathologic angiogenesis, thus guaranting the safety when using this drug in ROP ( Hoppe et al, 2020 ).…”

“…Thus, various mechanisms proved at different extent that HIF-PHIs showed retinal protection effect. Since ROP is predictable and the protection effect is mediated by liver and local retinal synchronously, it is suggested that HIF-PHIs administered systemically, starting at birth, continuing at 4–7 days intervals until 30 weeks, when the earliest stages of ROP can be seen ( Hoppe et al, 2020 ). While in RD and meibomian gland dysfunction, local preparation might be more favorable, and it is important to institute the therapeutic dosage and duration for treating the disease without obvious systemic effects.…”

Roxadustat: Not just for anemia

“…There is also evidence that the activation of HIF by roxadustat prevented oxygen-induced retinopathy in animal models, suggesting its possible use for prevention of childhood blindness ( Hoppe et al, 2016 ; Liu et al, 2016 ). Another study of ROP found that roxadustat stably increased the expression of glycolysis-related genes by inducing HIF-1α, which improved retinal metabolism and normalized angiogenesis ( Hoppe et al, 2020 ). An elevated level of HIF-2α contributes to angiogenesis during retinopathy, and roxadustat provides a weak induction of HIF-2α in retinal cells, thus suggesting the safety of this drug for treatment of ROP ( Hoppe et al, 2020 ).…”

“…Another study of ROP found that roxadustat stably increased the expression of glycolysis-related genes by inducing HIF-1α, which improved retinal metabolism and normalized angiogenesis ( Hoppe et al, 2020 ). An elevated level of HIF-2α contributes to angiogenesis during retinopathy, and roxadustat provides a weak induction of HIF-2α in retinal cells, thus suggesting the safety of this drug for treatment of ROP ( Hoppe et al, 2020 ). Zhou et al (2019) examined a rat subcutaneous cavity model and showed that roxadustat promoted angiogenesis and maturation in vitro and in vivo , suggesting it may be useful during tissue transplantation.…”

Metabolism in Retinopathy of Prematurity

“…Usui-Ouchi et al reported that intravitreal injection of peptides derived from intrinsically disordered protein CITED2, a negative feedback regulator for HIF activation, inhibited retinal neovascularization and vaso-obliteration in OIR [76]. Meanwhile, Hoppe et al suggested that stabilizing HIF-1 during the hyperoxic phase prevents vaso-obliteration and subsequent neovascularization in OIR mice [77]. Elevated aerobic glycolysis in response to HIF stabilization with HIF prolyl hydroxylase inhibitors before or during hyperoxia might contribute to the neurovascular protection of retina in OIR mice [78,79].…”