Prolyl hydroxylase inhibition during hyperoxia prevents oxygen-induced retinopathy.
Oxygen-induced retinopathy (OIR) in the mouse, like the analogous human disease retinopathy of prematurity, is an ischemic retinopathy dependent on oxygen-induced vascular obliteration. We tested the hypothesis that chemically overriding the oxygen-induced downregulation of hypoxia-inducible factor (HIF) activity would prevent vascular obliteration and subsequent pathologic neovascularization in the OIR model. Because the degradation of HIF-1alpha is regulated by prolyl hydroxylases, we examined the effect of systemic administration of a prolyl hydroxylase inhibitor, dimethyloxalylglycine, in the OIR model. Our results determine that stabilizing HIF activity in the early phase of OIR prevents the oxygen-induced central vessel loss and subsequent vascular tortuosity and tufting that is characteristic of OIR. Overall, these findings imply that simulating hypoxia chemically by stabilizing HIF activity during the causative ischemia phase (hyperoxia) of retinopathy of prematurity may be of therapeutic value in preventing progression to the proliferative stage of the disease.
Sears
Jonathan E
JE
Department of Ophthalmic Research, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic Foundation, Cleveland OH 44195, USA. searsj@ccf.org
Hoppe
George
G
Ebrahem
Quteba
Q
Anand-Apte
Bela
B
D000332:Aerobiosis; D000600:Amino Acids, Dicarboxylic / Q000008:administration & dosage*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D004921:Erythropoietin / Q000096:biosynthesis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007231:Infant, Newborn; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D010100:Oxygen / Q000633:toxicity*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D012178:Retinopathy of Prematurity / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D000099162:Endothelial PAS Domain-Containing Protein 1
D000600:Amino Acids, Dicarboxylic; D051792:Basic Helix-Loop-Helix Proteins; D004791:Enzyme Inhibitors; D004921:Erythropoietin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D011393:Procollagen-Proline Dioxygenase; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C040947:oxalylglycine