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Suppression of aberrant choroidal neovascularization through activation of the aryl hydrocarbon receptor.

Publication ,  Journal Article
Choudhary, M; Safe, S; Malek, G
Published in: Biochim Biophys Acta Mol Basis Dis
May 2018

The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor, initially discovered for its role in regulating xenobiotic metabolism. There is extensive evidence supporting a multi-faceted role for AhR, modulating physiological pathways important in cell health and disease. Recently we demonstrated that the AhR plays a role in the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We found that loss of AhR exacerbates choroidal neovascular (CNV) lesion formation in a murine model. Herein we tested the therapeutic impact of AhR activation on CNV lesion formation and factors associated with aberrant neovascularization. We screened a panel of synthetic drugs and endogenous AhR ligands, assessed their ability to activate AhR in choroidal endothelial cells, and inhibit angiogenesis in vitro. Drugs with an anti-angiogenic profile were then administered to a murine model of CNV. Two compounds, leflunomide and flutamide, significantly inhibited CNV formation concurrent with positive modifying effects on angiogenesis, inflammation, extracellular matrix remodeling, and fibrosis. These results validate the role of the AhR pathway in regulating CNV pathogenesis, identify mechanisms of AhR-based therapies in the eye, and argue in favor of developing AhR as a drug target for the treatment of neovascular AMD.

Duke Scholars

Published In

Biochim Biophys Acta Mol Basis Dis

DOI

ISSN

0925-4439

Publication Date

May 2018

Volume

1864

Issue

5 Pt A

Start / End Page

1583 / 1595

Location

Netherlands

Related Subject Headings

  • Receptors, Aryl Hydrocarbon
  • Mice, Knockout
  • Mice
  • Macular Degeneration
  • Macaca mulatta
  • Endothelial Cells
  • Choroidal Neovascularization
  • Cell Line
  • Biochemistry & Molecular Biology
  • Animals
 

Citation

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Chicago
ICMJE
MLA
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Choudhary, M., Safe, S., & Malek, G. (2018). Suppression of aberrant choroidal neovascularization through activation of the aryl hydrocarbon receptor. Biochim Biophys Acta Mol Basis Dis, 1864(5 Pt A), 1583–1595. https://doi.org/10.1016/j.bbadis.2018.02.015
Choudhary, Mayur, Stephen Safe, and Goldis Malek. “Suppression of aberrant choroidal neovascularization through activation of the aryl hydrocarbon receptor.Biochim Biophys Acta Mol Basis Dis 1864, no. 5 Pt A (May 2018): 1583–95. https://doi.org/10.1016/j.bbadis.2018.02.015.
Choudhary M, Safe S, Malek G. Suppression of aberrant choroidal neovascularization through activation of the aryl hydrocarbon receptor. Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt A):1583–95.
Choudhary, Mayur, et al. “Suppression of aberrant choroidal neovascularization through activation of the aryl hydrocarbon receptor.Biochim Biophys Acta Mol Basis Dis, vol. 1864, no. 5 Pt A, May 2018, pp. 1583–95. Pubmed, doi:10.1016/j.bbadis.2018.02.015.
Choudhary M, Safe S, Malek G. Suppression of aberrant choroidal neovascularization through activation of the aryl hydrocarbon receptor. Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt A):1583–1595.
Journal cover image

Published In

Biochim Biophys Acta Mol Basis Dis

DOI

ISSN

0925-4439

Publication Date

May 2018

Volume

1864

Issue

5 Pt A

Start / End Page

1583 / 1595

Location

Netherlands

Related Subject Headings

  • Receptors, Aryl Hydrocarbon
  • Mice, Knockout
  • Mice
  • Macular Degeneration
  • Macaca mulatta
  • Endothelial Cells
  • Choroidal Neovascularization
  • Cell Line
  • Biochemistry & Molecular Biology
  • Animals