title: Beta-lapachone inhibits pathological retinal neovascularization in oxygen-induced retinopathy via regulation of HIF-1α.
abstract: Retinal neovascularization in retinopathy of prematurity (ROP) is the most common cause of blindness for children. Despite evidence that hypoxia inducible factor (HIF)-1α -VEGF axis is associated with the pathogenesis of ROP, the inhibitors of HIF-1α have not been established as a therapeutic target in the control of ROP pathophysiology. We investigated the hypothesis that degradation of HIF-1α as a master regulator of angiogenesis in hypoxic condition, using β-lapachone, would confer protection against hypoxia-induced retinopathy without affecting physiological vascular development in mice with oxygen-induced retinopathy (OIR), an animal model of ROP. The effects of β-lapachone were examined after intraocular injection in mice with OIR. Intraocular administration of β-lapachone resulted in significant reduction in hypoxia-induced retinal neovascularization without retinal toxicity or perturbation of developmental retinal angiogenesis. Our results demonstrate that HIF-1α-mediated VEGF expression in OIR is associated with pathological neovascularization, not physiological angiogenesis. Thus, strategies blocking HIF-1α in the developing eye in the pathological hypoxia could serve as a novel therapeutic target for ROP.
authors.affiliation: Fight against Angiogenesis-Related Blindness Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Korea; Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Sung Wook
authors.initials: SW
authors.lastname: Park
authors.forename: Jin Hyoung
authors.initials: JH
authors.lastname: Kim
authors.forename: Ko-Eun
authors.initials: KE
authors.lastname: Kim
authors.forename: Moon Hee
authors.initials: MH
authors.lastname: Jeong
authors.forename: Hyunsung
authors.initials: H
authors.lastname: Park
authors.forename: Bongju
authors.initials: B
authors.lastname: Park
authors.forename: Young-Ger
authors.initials: YG
authors.lastname: Suh
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Park
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D056965:Injections, Intraocular; D008810:Mice, Inbred C57BL; D009285:Naphthoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D010100:Oxygen; D059748:Proteolysis / Q000187:drug effects; D012160:Retina / Q000187:drug effects / Q000473:pathology; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D014158:Transcription, Genetic / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009285:Naphthoquinones; D042461:Vascular Endothelial Growth Factor A; C014638:beta-lapachone; D010100:Oxygen
keywords: hypoxia-induced factor 1-α; oxygen-induced retinopathy; retinal neovascularization; retinopathy of prematurity; vascular endothelial growth factor; β-lapachone