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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Choudhary, M; Safe, S; Malek, G

Published Date

  • May 2018

Published In

Volume / Issue

  • 1864 / 5 Pt A

Start / End Page

  • 1583 - 1595

PubMed ID

  • 29481912

Pubmed Central ID

  • 29481912

International Standard Serial Number (ISSN)

  • 0925-4439

Digital Object Identifier (DOI)

  • 10.1016/j.bbadis.2018.02.015

Language

  • eng

Conference Location

  • Netherlands