HES1 promotes extracellular matrix protein expression and inhibits proliferation and migration in human trabecular meshwork cells under oxidative stress

Oncotarget. 2017 Mar 28;8(13):21818-21833. doi: 10.18632/oncotarget.15631.

Abstract

Glaucoma is the leading cause of irreversible blindness. The most prevalent form of glaucoma is primary open-angle glaucoma (POAG). Oxidative stress is one of the major pathogenic factors of the POAG, and can elicit molecular and functional changes in trabecular meshwork cells, causing increased aqueous humor outflow resistance and elevated intraocular pressure. However, the regulatory mechanisms underlying oxidative stress-induced cell phenotypic changes remain elusive. Herein, we exposed primary human trabecular meshwork cells to the oxidative stress induced by 300 μM H2O2 for 2 h, and found significantly up-regulated expression of extracellular matrix proteins and a transcription factor, hairy and enhancer of split-1 (HES1). The cell functions, including migration and proliferation, were impaired by the oxidative stress. Furthermore, HES1 shRNA abrogated the extracellular matrix protein up-regulation and rescued the functional defects caused by the oxidative stress; conversely, HES1 overexpression resulted in the molecular and functional changes similar to those induced by H2O2. These results suggest that HES1 promotes extracellular matrix protein expression and inhibits proliferative and migratory functions in the trabecular meshwork cells under oxidative stress, thereby providing a novel pathogenic mechanism underlying and a potential therapeutic target to the POAG.

Keywords: HES1; extracellular matrix; glaucoma; oxidative stress; trabecular meshwork.

MeSH terms

  • Blotting, Western
  • Cell Movement* / physiology
  • Cell Proliferation* / physiology
  • Extracellular Matrix / metabolism
  • Extracellular Matrix / pathology*
  • Fluorescent Antibody Technique
  • Gene Knockdown Techniques
  • Glaucoma, Open-Angle / metabolism
  • Glaucoma, Open-Angle / pathology*
  • Humans
  • Oxidative Stress / physiology*
  • Real-Time Polymerase Chain Reaction
  • Trabecular Meshwork / metabolism
  • Trabecular Meshwork / pathology*
  • Transcription Factor HES-1 / metabolism*

Substances

  • Transcription Factor HES-1
  • HES1 protein, human