Comparative systems pharmacology of HIF stabilization in the prevention of retinopathy of prematurity.
Retinopathy of prematurity (ROP) causes 100,000 new cases of childhood blindness each year. ROP is initiated by oxygen supplementation necessary to prevent neonatal death. We used organ systems pharmacology to define the transcriptomes of mice that were cured of oxygen-induced retinopathy (OIR, ROP model) by hypoxia-inducible factor (HIF) stabilization via HIF prolyl hydroxylase inhibition using the isoquinolone Roxadustat or the 2-oxoglutarate analog dimethyloxalylglycine (DMOG). Although both molecules conferred a protective phenotype, gene expression analysis by RNA sequencing found that Roxadustat can prevent OIR by two pathways: direct retinal HIF stabilization and induction of aerobic glycolysis or indirect hepatic HIF-1 stabilization and increased serum angiokines. As predicted by pathway analysis, Roxadustat rescued the hepatic HIF-1 knockout mouse from retinal oxygen toxicity, whereas DMOG could not. The simplicity of systemic treatment that targets both the liver and the eye provides a rationale for protecting the severely premature infant from oxygen toxicity.
Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195; Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195;
George
G
Hoppe
Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195;
Suzy
S
Yoon
Yorg Corporation, Plano, TX 75093;
Banu
B
Gopalan
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065;
Alexandria R
AR
Savage
Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195;
Rebecca
R
Brown
Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195;
Kelsey
K
Case
ImageIQ Inc., Cleveland, OH 44128;
Amit
A
Vasanji
Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
E Ricky
ER
Chan
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065;
Randi B
RB
Silver
Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195; Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195; searsj@ccf.org.
Jonathan E
JE
Sears
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007546:Isoquinolines / Q000008:administration & dosage*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012160:Retina / Q000187:drug effects / Q000378:metabolism*; D012178:Retinopathy of Prematurity / Q000188:drug therapy* / Q000517:prevention & control*; D059467:Transcriptome / Q000187:drug effects*; D016896:Treatment Outcome
D051793:Hypoxia-Inducible Factor 1; D007546:Isoquinolines; D005998:Glycine; C584543:roxadustat
BPD; HIF; ROP; Roxadustat; prolyl hydroxylase inhibition