April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Deletion of Thioredoxin Interacting Protein (TXNIP) Augments Hyperoxia-induced Vaso-obliteration in Ischemic Retinopathy.
Author Affiliations & Notes
  • Azza B El-Remessy
    Clin & Experimental Therapeutics, University of Georgia, Augusta, GA
    Culver VDI, Georgia Regents University, Augusta, GA
  • Mohammed A Abdelsaid
    Clin & Experimental Therapeutics, University of Georgia, Augusta, GA
    Physiology, Georgia Regents University, Augusta, GA
  • Adviye Ergul
    Clin & Experimental Therapeutics, University of Georgia, Augusta, GA
    Physiology, Georgia Regents University, Augusta, GA
  • Suraporn Matragoon
    Clin & Experimental Therapeutics, University of Georgia, Augusta, GA
    Culver VDI, Georgia Regents University, Augusta, GA
  • Footnotes
    Commercial Relationships Azza El-Remessy, None; Mohammed Abdelsaid, None; Adviye Ergul, None; Suraporn Matragoon, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 3020. doi:https://doi.org/
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      Azza B El-Remessy, Mohammed A Abdelsaid, Adviye Ergul, Suraporn Matragoon; Deletion of Thioredoxin Interacting Protein (TXNIP) Augments Hyperoxia-induced Vaso-obliteration in Ischemic Retinopathy.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3020. doi: https://doi.org/.

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

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Abstract

Purpose: We have recently shown that thioredoxin interacting protein (TXNIP) is required for VEGF-mediated VEGFR2 receptor activation and angiogenic signal. Retinas from TXNIP knockout mice (TKO) exhibited higher cellular antioxidant defense compared to wild type (WT). The current study was undertaken to examine the impact of TXNIP deletion on hyperoxia-induced vaso-obliteration in ischemic retinopathy model.

Methods: TKO and WT pups were subjected to oxygen-induced retinopathy model. Retinal central capillary dropout was measured at p12. Retinal redox and nitrative state were assessed by reduced-glutathione (GSH), thioredoxin reductase activity and nitrotyrosine formation. Western blot and QT-PCR were used to assess VEGF, VEGFR-2, Akt, iNOS and eNOS, thioredoxin expression, ASK-1 activation and downstream cleaved caspase-3 and PARP in retinal lysates.

Results: Retinas from TKO mice exposed to hyperoxia showed significant increases (1.5-fold) in vaso-obliteration as indicated by central capillary drop out area compared to WT. Retinas from TKO showed minimal nitrotyrosine levels (10% of WT) with no change in eNOS or iNOS mRNA expression. There was no change in levels of VEGF or activation of VEGFR2 and its downstream Akt in retinas from TKO and WT. In comparison to WT, retinas from TKO showed significantly higher level of GSH and thioredoxin reductase activity in normoxia but comparable levels under hyperoxia. Exposure of TKO to hyperoxia significantly decreased the anti-apoptotic thioredoxin protein (~50%) level compared with WT. This effect was associated with a significant increase in activation of the apoptotic ASK-1, PARP and caspase-3 pathway.

Conclusions: Our results showed that despite comparable VEGF level and signal in TKO, exposure to hyperoxia significantly decreased Trx expression compared to WT. This effect resulted in liberation and activation of the apoptotic ASK-1 signal. These findings suggest that TXNIP is required for endothelial cell survival and homeostasis especially under stress conditions including hyperoxia.

Keywords: 426 apoptosis/cell death • 748 vascular endothelial growth factor • 634 oxidation/oxidative or free radical damage  
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