National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China.
Redox Biol. 2019 Jan;20:46-59. doi: 10.1016/j.redox.2018.09.021. Epub 2018 Sep 26.
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 HO 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.
高同型半胱氨酸血症（HHcy）引起的内皮功能障碍在血管病变中起着关键作用。然而，内质网（ER）氧化还原稳态在 HHcy 诱导的内皮功能障碍中的作用知之甚少。在这里，我们表明 Hcy 通过促进缺氧诱导因子 1α与 ERO1A 启动子结合，在人脐静脉内皮细胞和 HHcy 小鼠的动脉中诱导 ER 氧化还原还原酶 1α（Ero1α）表达和 ER 应激和炎症。Hcy 通过增加 Ero1α 的表达来提高 ER 中的 GSH/GSSG 比值，从而变构激活 Ero1α 产生 HO 并引发 ER 氧化应激。相比之下，HHcy 小鼠中由 ER 谷胱甘肽过氧化物酶 7（GPx7）介导的抗氧化途径被下调。Ero1α 敲低和 GPx7 过表达可保护内皮细胞免受 HHcy 诱导的 ER 氧化应激和炎症。我们的工作表明，靶向 ER 氧化还原稳态可以作为 HHcy 相关血管疾病的干预措施。
