Abstract：
Atherosclerosis refers to a disease characterized by the formation of lipid plaque deposits within arterial walls, leading to reduced blood flow or blockage of blood outflow. The process of endothelial injury induced by oxidized low-density lipoprotein (ox-LDL) is considered the initial stage of atherosclerosis. Ferroptosis is a form of iron-dependent, non-apoptotic cell death, and current research suggests its association with coronary artery disease (CAD). In this study, we observed a correlation between reduced expression of SREBP-1 and the occurrence of stable CAD. Additionally, during the process of endothelial injury induced by ox-LDL, we also noted decreased expression of the SREBP-1/SCD1/FADS2 and involvement in the ferroptosis process. Mechanistically, ox-LDL induced endothelial injury by inhibiting the lipid biosynthesis process mediated by the SREBP-1/SCD1/FADS2, thereby inducing lipid peroxidation and ferroptosis. On the contrary, overexpression of SREBP-1 or supplementation with monounsaturated fatty acids counteracted iron accumulation, mitochondrial damage, and lipid peroxidation-induced ferroptosis, thereby improving endothelial injury. Our study indicated that the decreased expression of peripheral blood SREBP-1 mRNA is an independent risk factor for stable CAD. Furthermore, in endothelial cells, the lipid biosynthesis process mediated by SREBP-1 could ameliorate endothelial injury by resisting ferroptosis. The study has been registered with the Chinese Clinical Trial Registry, which serves as a primary registry in the World Health Organization International Clinical Trials Registry Platform (ChiCTR2300074315, August 3rd, 2023).
摘要：
动脉粥样硬化是指以在动脉壁内形成脂质斑块沉积物为特征的疾病。导致血流量减少或血液流出阻塞。氧化低密度脂蛋白（ox-LDL）诱导的内皮损伤过程被认为是动脉粥样硬化的初始阶段。铁凋亡是一种依赖铁的形式，非凋亡性细胞死亡，目前的研究表明其与冠状动脉疾病（CAD）有关。在这项研究中,我们观察到SREBP-1表达降低与稳定型CAD发生之间存在相关性。此外,在ox-LDL诱导的内皮损伤过程中，我们还注意到SREBP-1/SCD1/FADS2的表达降低，并参与了铁凋亡过程。机械上,ox-LDL通过抑制SREBP-1/SCD1/FADS2介导的脂质生物合成过程，从而诱导脂质过氧化和铁凋亡，从而诱导内皮损伤。相反,SREBP-1的过表达或补充单不饱和脂肪酸可抵消铁的积累，线粒体损伤，和脂质过氧化诱导的铁死亡，从而改善内皮损伤。我们的研究表明，外周血SREBP-1mRNA的表达降低是冠心病稳定期的独立危险因素。此外，在内皮细胞中，SREBP-1介导的脂质生物合成过程可以通过抵抗铁凋亡来改善内皮损伤。该研究已在中国临床试验注册中心注册，作为世界卫生组织国际临床试验注册平台的主要注册中心(ChiCTR2300074315，8月3日，2023年）。
