biostudies-literatureWu XChinese Academy of SciencesNational Key Clinical Specialty Discipline Construction Program of ChinaNational Natural Science Foundation of ChinaYouth Innovation Promotion Association of the Chinese Academy of Sciences46-59https://www.ebi.ac.uk/biostudies/studies/S-EPMC6174864biostudies-literatureUnknown20Endothelial 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 peroxidRedox biologyHomocysteine causes vascular endothelial dysfunction by disrupting endoplasmic reticulum redox homeostasis.PMC617486431571163817704452016YFA05002002017YFA05040003177126191439206Yang JFeng JMiao YZhang LWang XWang CCWu XWang LfalseHomocysteine 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-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 peroxid2019-01-01T00:00:00Z2019 Jan2026-06-13T04:08:41.247Z2019-03-26T23:59:45ZS-EPMC61748643029294510.1016/j.redox.2018.09.021