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Keywords:

  • epigenetics;
  • histone lysine demethylase;
  • hypoxia;
  • HIF signaling;
  • berberine

Abstract

Preclinical Research

Pathological neovascularization during ischemic retinopathies is the major cause of blindness. The underlying cause of neovascularization is activation of the hypoxia-inducible factor (HIF) pathway leading to expression of pro-angiogenic factors. Recent studies have established that histone lysine demethylases (KDMs) play an important role in the HIF-mediated expression of pro-angiogenic factors under hypoxic conditions. Thus, inhibitors of the HIF pathway can be used for the treatment of these debilitating diseases. Here, we show that berberine, a plant alkaloid with a long history of medicinal use, is a potent inhibitor of the HIF pathway and hypoxia-induced expression of KDMs in a number of retinal pigment epithelial and cancer cell lines. Treating these cells with berberine leads to inhibition of KDMs-mediated induction of pro-angiogenic genes (adrenomedullin and growth differentiation factor 15) under hypoxic conditions. Because berberine has been used in eyedrops to treat trachoma, our results suggest that its proper delivery to the back of the eye may treat retinal and choroidal neovascularization during ischemic retinopathies.