同型半胱氨酸代谢异常所导致的高同型半胱氨酸血症（Hyperhomocysteinemia, HHcy）已被证实是包括心血管疾病在内的许多疾病的危险因素。血管内皮细胞功能损伤是HHcy导致血管病变的重要原因，其可能的机制包括氧化应激、内质网应激和炎症反应等。本项目以内质网氧化还原稳态维持系统为切入点，拟深入研究HHcy引起血管内皮细胞内质网过氧化所引起的内质网氧化应激，从而导致内皮细胞功能紊乱和血管病变的分子机制、调控网络和关键节点。具体研究：1）HHcy在血管内皮细胞中通过改变内质网氧化还原平衡激活巯基氧化酶Ero1α的分子机制；2）HHcy通过缺氧诱导因子HIF-1α上调Ero1α产生内质网氧化应激的分子机制；3）抗氧化转录因子Nrf2介导内质网过氧化物酶GPx7对HHcy引起的内质网氧化应激的保护作用。本研究将为HHcy导致心血管疾病的致病机制和医疗干预提供新的理论基础和实验依据。

Hyperhomocysteinemia (HHcy), caused by abnormal metabolism of homocysteine, is a risk factor for many diseases, e. g. cardiovascular disease. Vascular endothelial cell dysfunction is an important reason for HHcy-induced vasculopathy, and may result from oxidative stress, endoplasmic reticulum (ER) stress and inflammation. In this project, we focus on the ER redox homeostasis system, aiming to study the ER overoxidation-derived ER oxidative stress in vascular endothelial cells induced by HHcy, and to reveal the underlying molecular mechanisms, regulation network and key nodes. In particular, we will study: 1) how HHcy perturbs the ER redox balance then activates sulfhydryl oxidase Ero1α in endothelial cell; 2) how HHcy up-regulates Ero1α via hypoxia-inducible factor HIF-1α and results in ER oxidative stress; 3) the protective function of the ER-located peroxidase GPx7 in HHcy-induced ER oxidative stress, mediated by antioxidant transcription factor Nrf2. This work will provide novel theoretical basis and experimental evidences for the pathogenic mechanism and medical intervention of HHcy-induced cardiovascular disease.