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Proc Natl Acad Sci U S A. 2016 May 3;113(18):E2516-25. doi: 10.1073/pnas.1523005113. Epub 2016 Apr 18.

Comparative systems pharmacology of HIF stabilization in the prevention of retinopathy of prematurity.

Author information

1
Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195; Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195;
2
Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195;
3
Yorg Corporation, Plano, TX 75093;
4
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065;
5
ImageIQ Inc., Cleveland, OH 44128;
6
Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
7
Cole Eye Institute, Cleveland Clinic, Cleveland, OH 44195; Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195; searsj@ccf.org.

Abstract

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.

KEYWORDS:

BPD; HIF; ROP; Roxadustat; prolyl hydroxylase inhibition

PMID:
27091985
PMCID:
PMC4983815
DOI:
10.1073/pnas.1523005113
[Indexed for MEDLINE]
Free PMC Article

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