Cao Minghua, Li Mengqing, Li Xixuan, Li Yuanyuan, Chen Yunyun, Drekolia Maria-Kyriaki, Cheng Xiang, Lagos Fredy Delgado, Bibli Sofia-Iris, Hu Jiong
Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Sino-German Laboratory of CardioPulmonary Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Vascular Dysfunction, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Redox Biol. 2025 Jun 14;85:103730. doi: 10.1016/j.redox.2025.103730.
Atheroslcerosis manifests as localized lesions within the vascular tree, preferentially affecting arteries at branch points, the outer wall of bifurcations and the inner walls of curvatures. Such spatial localized sensitivity to atherosclerosis, can be partially attributed to endothelial cell heterogeneity which compromises vascular fitness and contributes to the pathogenesis of the diseases. Here we identified that in a subcluster of aortic endothelial cells characterized with atheroprone gene signatures, the polyunsaturated fatty acids (PUFAs) metabolic enzyme soluble epoxide hydrolase (sEH) is selectively upregulated. Genetic endothelial-specific overexpression of the sEH resulted in excessive and accelerated atherosclerosis development, while inducible endothelial-specific deletion of sEH protected against PCSK9 mediated atherosclerotic plaque formation. Mechanistically, sEH-derived docosahexaenoic acid (DHA) diol (19,20-DHDP) disrupts mitochondrial protein-cholesterol associations in endothelial cells, which through reduced oxidizing metabolic import of pyruvate and malate inhibited mitochondrial Complex I activity. Such inhibition, resulted in a lowering of the mitochondrial membrane potential and subsequent excessive mitochondrial reactive oxygen species production and disrupted mitochondrial structure. Heightened mitochondrial redox generation ultimately led to TGFβ activation and the subsequent stimulation of an athroprone and pro-inflammatory endothelial transcriptional programme. Re-establishing redox homeostasis by antioxidant treatments, halted the atheroprone phenotypes of sEH overexpressing vessels. Our data propose that manipulating endothelial PUFA metabolism and sEH activity in the endothelium can exert vascular protective effects.
动脉粥样硬化表现为血管系统内的局部病变，优先影响分支点处的动脉、分叉的外壁和曲率的内壁。这种对动脉粥样硬化的空间局部敏感性，部分可归因于内皮细胞异质性，它损害血管健康并促成疾病的发病机制。在这里，我们发现，在具有动脉粥样硬化倾向基因特征的主动脉内皮细胞亚群中，多不饱和脂肪酸（PUFA）代谢酶可溶性环氧化物水解酶（sEH）被选择性上调。sEH的遗传内皮特异性过表达导致动脉粥样硬化过度且加速发展，而诱导性内皮特异性缺失sEH则可预防PCSK9介导的动脉粥样硬化斑块形成。从机制上讲，sEH衍生的二十二碳六烯酸（DHA）二醇（19,20-DHDP）破坏内皮细胞中的线粒体蛋白-胆固醇结合，这通过减少丙酮酸和苹果酸的氧化代谢输入抑制线粒体复合体I活性。这种抑制导致线粒体膜电位降低，随后线粒体活性氧过度产生并破坏线粒体结构。线粒体氧化还原生成增强最终导致TGFβ激活，并随后刺激动脉粥样硬化倾向和促炎的内皮转录程序。通过抗氧化剂治疗重新建立氧化还原稳态，可阻止sEH过表达血管的动脉粥样硬化倾向表型。我们的数据表明，在内皮中操纵内皮PUFA代谢和sEH活性可发挥血管保护作用。
