April 2014
Volume 55, Issue 13
ARVO Annual Meeting Abstract  |   April 2014
Identification of HIF-mediated Liver-specific Transcripts Associated with the Systemic Pharmacological Preconditioning against Ischemic Retinopathy
Author Affiliations & Notes
  • George Hoppe
    Cole Eye Institute, Cleveland Clinic, Cleveland, OH
  • Banu Gopalan
    Yorg Corporation, Plano, TX
  • Jonathan E Sears
    Cole Eye Institute, Cleveland Clinic, Cleveland, OH
  • Footnotes
    Commercial Relationships George Hoppe, None; Banu Gopalan, None; Jonathan Sears, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 5378. doi:
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      George Hoppe, Banu Gopalan, Jonathan E Sears; Identification of HIF-mediated Liver-specific Transcripts Associated with the Systemic Pharmacological Preconditioning against Ischemic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5378.

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

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Purpose: Systemic administration of prolyl hydroxylase inhibitor DMOG protects retinal vasculature from oxygen-induced vaso-obliteration in the mouse model of retinopathy of prematurity (ROP). The protective effect of DMOG is associated with a significant and selective induction of HIF-mediated gene expression in the liver. The purpose of this study was to identify HIF-dependent hepatic transcriptome that can be functionally linked to protecting retinal capillaries from oxygen toxicity.

Methods: Microarray analysis was performed on RNA isolated from 4 groups of mouse pups (postnatal age of 8 days): wild type C57BL6 (WT) or conditional liver HIF-1α knockout (LHKO) each injected with either PBS or DMOG. Total RNA was converted to cDNA, labeled and hybridized to the MouseRef-8 Expression BeadChip from Illumina. Raw data was pre-processed (QC, log 2 transformation, quantile normalization) and subjected to statistical analysis (Empirical Bayes method) to identify differentially expressed genes (DEGs) amongst the 4 groups. DEGs were defined as those with FDR p value <= 0.05 and fold change >= 1.5. In silico analyses of affected pathways and functions were performed using both licensed as well as open-access software tools and databases (IPA, Metacore, MGI, DAVID, etc.).

Results: Our strategy comprised of 1) obtaining separate lists of DEGs affected by DMOG for WT and LHKO, respectively; then 2) superimposing these list to identify DEGs exclusive to WT. DMOG injection upregulated 66 genes and downregulated 98 genes in the WT liver, while 51 genes were up and 80 genes were down in the LHKO liver. Upon further functional profiling, genes that were uniquely upregulated in the WT (47) fell into several major categories, most prominent being predictable “angiogenesis”, as well as unanticipated “fatty acid metabolism”. Importantly, the former group included genes previously implicated in experimental and clinical ROP, i.e., IGF1, ANGPTL3, DDIT4, ADORA1, FLT1, further validating our molecular screening.

Conclusions: Comparative gene expression profiling identified angiogenic and metabolic HIF-dependent transcripts elevated in the liver following systemic prolyl hydroxylase inhibition, which in turn ameliorates the mouse model of ROP. These results lend support to the endocrine role of the liver in protecting distal capillary beds against ischemic vasculopathy.

Keywords: 706 retinopathy of prematurity • 548 hypoxia • 739 transcription factors  

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