Homocysteine causes vascular endothelial dysfunction by disrupting endoplasmic reticulum redox homeostasis

Redox Biol. 2019 Jan:20:46-59. doi: 10.1016/j.redox.2018.09.021. Epub 2018 Sep 26.

Abstract

Endothelial dysfunction induced by hyperhomocysteinemia (HHcy) plays a critical role in vascular pathology. However, little is known about the role of endoplasmic reticulum (ER) redox homeostasis in HHcy-induced endothelial dysfunction. Here, we show that Hcy induces ER oxidoreductin-1α (Ero1α) expression with ER stress and inflammation in human umbilical vein endothelial cells and in the arteries of HHcy mice. Hcy upregulates Ero1α expression by promoting binding of hypoxia-inducible factor 1α to the ERO1A promoter. Notably, Hcy rather than other thiol agents markedly increases the GSH/GSSG ratio in the ER, therefore allosterically activating Ero1α to produce H2O2 and trigger ER oxidative stress. By contrast, the antioxidant pathway mediated by ER glutathione peroxidase 7 (GPx7) is downregulated in HHcy mice. Ero1α knockdown and GPx7 overexpression protect the endothelium from HHcy-induced ER oxidative stress and inflammation. Our work suggests that targeting ER redox homeostasis could be used as an intervention for HHcy-related vascular diseases.

Keywords: Endoplasmic reticulum; Endothelial cells; Ero1α; GPx7; Homocysteine; Redox homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endoplasmic Reticulum / metabolism*
  • Endothelial Cells / metabolism*
  • Endothelium, Vascular / metabolism*
  • Homeostasis*
  • Homocysteine / metabolism*
  • Humans
  • Oxidation-Reduction*
  • Reactive Oxygen Species / metabolism

Substances

  • Reactive Oxygen Species
  • Homocysteine