Homocysteine causes vascular endothelial dysfunction by disrupting endoplasmic reticulum redox homeostasis

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-1 alpha (Ero1 alpha) expression with ER stress and inflammation in human umbilical vein endothelial cells and in the arteries of HHcy mice. Hcy upregulates Ero1 alpha expression by promoting binding of hypoxia-inducible factor 1 alpha to the ERO1A promoter. Notably, Hcy rather than other thiol agents markedly increases the GSH/GSSG ratio in the ER, therefore allosterically activating Ero1 alpha 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. Ero1 alpha knockdown and GPx7 over expression 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.