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

被引:98
作者
Hoppe, George [1 ,2 ]
Yoon, Suzy [1 ]
Gopalan, Banu [3 ]
Savage, Alexandria R. [4 ]
Brown, Rebecca [1 ]
Case, Kelsey [1 ]
Vasanji, Amit [5 ]
Chan, E. Ricky [6 ]
Silver, Randi B.
Sears, Jonathan E. [1 ,2 ]
机构
[1] Cleveland Clin, Cole Eye Inst, Cleveland, OH 44195 USA
[2] Cleveland Clin, Dept Cellular & Mol Med, Cleveland, OH 44195 USA
[3] Yorg Corp, Plano, TX 75093 USA
[4] Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10065 USA
[5] ImageIQ Inc, Cleveland, OH 44128 USA
[6] Case Western Reserve Univ, Sch Med, Inst Computat Biol, Cleveland, OH 44106 USA
关键词
HIF; BPD; prolyl hydroxylase inhibition; Roxadustat; ROP; OXYGEN-INDUCED-RETINOPATHY; ENDOTHELIAL GROWTH-FACTOR; PROLYL HYDROXYLASE INHIBITION; HUMAN ERYTHROPOIETIN GENE; HYPOXIA-INDUCIBLE FACTORS; RETINAL ANGIOGENESIS; MOUSE MODEL; EXPRESSION; HYPEROXIA; MICE;
D O I
10.1073/pnas.1523005113
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:E2516 / E2525
页数:10
相关论文
共 54 条
  • [1] The SLC16A Family of Monocarboxylate Transporters (MCTs)-Physiology and Function in Cellular Metabolism, pH Homeostasis, and Fluid Transport
    Adijanto, Jeffrey
    Philp, Nancy J.
    [J]. CO-TRANSPORT SYSTEMS, 2012, 70 : 275 - 311
  • [2] Aher SM, 2012, COCHRANE DB SYST REV, V10
  • [3] VASCULAR ENDOTHELIAL GROWTH-FACTOR IN OCULAR FLUID OF PATIENTS WITH DIABETIC-RETINOPATHY AND OTHER RETINAL DISORDERS
    AIELLO, LP
    AVERY, RL
    ARRIGG, PG
    KEYT, BA
    JAMPEL, HD
    SHAH, ST
    PASQUALE, LR
    THIEME, H
    IWAMOTO, MA
    PARK, JE
    NGUYEN, HV
    AIELLO, LM
    FERRARA, N
    KING, GL
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1994, 331 (22) : 1480 - 1487
  • [4] VASCULAR ENDOTHELIAL GROWTH-FACTOR ACTS AS A SURVIVAL FACTOR FOR NEWLY FORMED RETINAL-VESSELS AND HAS IMPLICATIONS FOR RETINOPATHY OF PREMATURITY
    ALON, T
    HEMO, I
    ITIN, A
    PEER, J
    STONE, J
    KESHET, E
    [J]. NATURE MEDICINE, 1995, 1 (10) : 1024 - 1028
  • [5] [Anonymous], 2014, COCHRANE DB SYST REV
  • [6] Activation of hypoxia-inducible factors in hyperoxia through prolyl 4-hydroxylase blockade in cells and explants of primate lung
    Asikainen, TM
    Schneider, BK
    Waleh, NS
    Clyman, RI
    Ho, WB
    Flippin, LA
    Günzler, V
    White, CW
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (29) : 10212 - 10217
  • [7] Cobalt stimulates HIF-1-dependent but inhibits HIF-2-dependent gene expression in liver cancer cells
    Befani, Christina
    Mylonis, Ilias
    Gkotinakou, Ioanna-Maria
    Georgoulias, Panagiotis
    Hu, Cheng-Jun
    Simos, George
    Liakos, Panagiotis
    [J]. INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 2013, 45 (11) : 2359 - 2368
  • [8] Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients
    Besarab, Anatole
    Provenzano, Robert
    Hertel, Joachim
    Zabaneh, Raja
    Klaus, Stephen J.
    Lee, Tyson
    Leong, Robert
    Hemmerich, Stefan
    Yu, Kin-Hung Peony
    Neff, Thomas B.
    [J]. NEPHROLOGY DIALYSIS TRANSPLANTATION, 2015, 30 (10) : 1665 - 1673
  • [9] BONIKOS DS, 1975, LAB INVEST, V32, P619
  • [10] ANGPTL3 stimulates endothelial cell adhesion and migration via integrin αvβ3 and induces blood vessel formation in vivo
    Camenisch, G
    Pisabarro, MT
    Sherman, D
    Kowalski, J
    Nagel, M
    Hass, P
    Xie, MH
    Gurney, A
    Bodary, S
    Liang, XH
    Clark, K
    Beresini, M
    Ferrara, N
    Gerber, HP
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (19) : 17281 - 17290