title: Inducing a visceral organ to protect a peripheral capillary bed: stabilizing hepatic HIF-1α prevents oxygen-induced retinopathy.
abstract: Activation of hypoxia-inducible factor (HIF) can prevent oxygen-induced retinopathy in rodents. Here we demonstrate that dimethyloxaloylglycine (DMOG)-induced retinovascular protection is dependent on hepatic HIF-1 because mice deficient in liver-specific HIF-1α experience hyperoxia-induced damage even with DMOG treatment, whereas DMOG-treated wild-type mice have 50% less avascular retina (P < 0.0001). Hepatic HIF stabilization protects retinal function because DMOG normalizes the b-wave on electroretinography in wild-type mice. The localization of DMOG action to the liver is further supported by evidence that i) mRNA and protein erythropoietin levels within liver and serum increased in DMOG-treated wild-type animals but are reduced by 60% in liver-specific HIF-1α knockout mice treated with DMOG, ii) triple-positive (Sca1/cKit/VEGFR2), bone-marrow-derived endothelial precursor cells increased twofold in DMOG-treated wild-type mice (P < 0.001) but are unchanged in hepatic HIF-1α knockout mice in response to DMOG, and iii) hepatic luminescence in the luciferase oxygen-dependent degradation domain mouse was induced by subcutaneous and intraperitoneal DMOG. These findings uncover a novel endocrine mechanism for retinovascular protection. Activating HIF in visceral organs such as the liver may be a simple strategy to protect capillary beds in the retina and in other peripheral tissues.
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: George
authors.initials: G
authors.lastname: Hoppe
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Lee
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Suzy
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Minzhong
authors.initials: M
authors.lastname: Yu
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio; Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio.
authors.forename: Neal S
authors.initials: NS
authors.lastname: Peachey
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Mary
authors.initials: M
authors.lastname: Rayborn
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: M Julieta
authors.initials: MJ
authors.lastname: Zutel
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: George
authors.initials: G
authors.lastname: Trichonas
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: John
authors.initials: J
authors.lastname: Au
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio; Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio. Electronic address: searsj@ccf.org.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Sears
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D018496:Hyperoxia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010100:Oxygen / Q000633:toxicity*; D012164:Retinal Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D000600:Amino Acids, Dicarboxylic; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004921:Erythropoietin; D010100:Oxygen; C040947:oxalylglycine
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