April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Gtx-822 a Selective Estrogen Receptor β (erβ) Ligand Protects Mitochondria in Arpe-19 Cells Through Genomic and Non-Genomic Pathways
Author Affiliations & Notes
  • J. R. Eswaraka
    Animal Resources, GTX Inc, Memphis, Tennessee
  • A. Giddabasappa
    Animal Resources, GTX Inc, Memphis, Tennessee
  • J. T. Dalton
    Animal Resources, GTX Inc, Memphis, Tennessee
  • M. Bauler
    Animal Resources, GTX Inc, Memphis, Tennessee
  • C. Barrett
    Animal Resources, GTX Inc, Memphis, Tennessee
  • Footnotes
    Commercial Relationships  J.R. Eswaraka, GTx Inc, F; GTx Inc, E; A. Giddabasappa, GTx Inc, F; GTx Inc, E; J.T. Dalton, GTx Inc, F; GTx Inc, E; M. Bauler, GTx Inc, F; GTx Inc, E; C. Barrett, GTx Inc, F; GTx Inc, E.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 6161. doi:
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      J. R. Eswaraka, A. Giddabasappa, J. T. Dalton, M. Bauler, C. Barrett; Gtx-822 a Selective Estrogen Receptor β (erβ) Ligand Protects Mitochondria in Arpe-19 Cells Through Genomic and Non-Genomic Pathways. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6161.

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

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Abstract

Introduction: : Aim:The goal of this study was to examine the role of an ERβ selective estrogen receptor modulator (SERM, GTx-822) in alleviating oxidative stress in ARPE-19 cells and to elucidate the molecular pathways involved in this protection.

Methods: : Cultured ARPE-19 cells were subjected to oxidative stress with t-butyl hydroxide (tBH) or hydrogen peroxide (H2O2) in the presence/absence of pharmacological doses of GTx-822. Reactive oxygen species (ROS) were measured using H2DCFDA fluorescence. Apoptosis was evaluated by cell-death ELISA kit and Hoechst-3486 staining. Mitochondrial membrane potential was measured using the JC-1 assay. Cellular localization of ER was evaluated by confocal microscopy. Gene expression and protein expression was quantitated using qRT-PCR and western blotting. Superoxide dismutase (SOD) and ATP levels were measured using commercial kits.

Results: : GTx-822 prevented oxidative stress in ARPE-19 cells in a dose dependent manner. This protective effect was reversed by antagonists of ERβ. GTx-822 preserved mitochondrial function through (a) induction of rapid signaling cascades including phosphorylation of ERK1/2, PI3K and Bad, and (b) Induction of phase II antioxidant genes and ERβ.

Conclusions: : This is the first report to show that an ERβ specific SERM can protect ARPE-19 cells from cellular degeneration induced by oxidative stress. GTx-822 mediated cytoprotection was mediated through induction of both genomic and non-genomic pathways. The results from this study open new avenues for use of SERMs in treatment of ocular diseases like AMD where oxidative stress plays a major role in disease pathology.

Keywords: age-related macular degeneration • oxidation/oxidative or free radical damage • mitochondria 
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