May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
2-Oxoglutarate Dioxygenase Inhibition During Hyperoxia Prevents Murine Retinopathy of Prematurity
Author Affiliations & Notes
  • Q. Ebrahem
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
  • G. Hoppe
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
  • B. Anand-Apte
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
  • J. E. Sears
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio
  • Footnotes
    Commercial Relationships  Q. Ebrahem, None; G. Hoppe, None; B. Anand-Apte, None; J.E. Sears, None.
  • Footnotes
    Support  Research to Prevent Blindness
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 2638. doi:https://doi.org/
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      Q. Ebrahem, G. Hoppe, B. Anand-Apte, J. E. Sears; 2-Oxoglutarate Dioxygenase Inhibition During Hyperoxia Prevents Murine Retinopathy of Prematurity. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2638. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : To investigate the effect of systemic, nonselective prolylhydroxylase inhibition during hyperoxia or Phase I of oxygen induced retinopathy (OIR) in C57Bl6 mouse.

Methods: : Aqueous solutions of dimethyloxaloglycine (DMOG) were injected intraperitoneally 24h prior to and 24h into hyperoxia using the standard mouse OIR model. Retinal flatmounts were prepared after intracardiac injection of Evans Blue dye and analyzed using fluorescent microscopy. Lysates of cultured human Mueller cells, retina, brain, liver, and kidney were probed with hypoxia inducible factor (HIF-1,-2) antibodies following DMOG treatment. Vascular endothelial growth factor (VEGF) and erythropoietin (Epo) ELISA of brain, retina, liver, and kidney and whole eye was used to measure concentration changes of these substances in response to DMOG.

Results: : Two hundred ug/gram body weight intraperitoneal injection of DMOG at P6 reduced capillary drop-out and vascular tortuosity by greater than 50% (p= 0.017 and 0.043), and 75% reduction in vascular tufts (p=2.7x10-7) in the mouse OIR model. Prevention of vasoobliteration was noted during hyperoxia within 24h of a single intraperitoneal (IP) DMOG injection. HIF-1 and HIF-2 were upregulated in cultured human Muller cells with expression peaking at 1uM DMOG. HIF-1 alpha expression was unchanged in eye, brain, and kidney 9h after intraperitoneal injection of DMOG, but increased in liver with a subsequent increase in hepatic VEGF expression. HIF-2 alpha expression increased only in kidney, correlating with massive renal erythropoietin expression within 6h of IP injection.

Conclusions: : Non-selective inhibition of a 2-oxoglutarate dioxygenase by DMOG ameliorates murine ROP by preventing oxygen induced vasoobliteration. The mechanism of action of DMOG is likely reversal of oxygen induced destabilization of extraocular HIF-1 and -2 with subsequent systemic upregulation of systemic erythropoietin and ocular VEGF during hyperoxia.

Keywords: retinopathy of prematurity • hypoxia • growth factors/growth factor receptors 
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