The activator protein-1 complex governs a vascular degenerative transcriptional programme in smooth muscle cells to trigger aortic dissection and rupture
The activator protein-1 complex governs a vascular degenerative transcriptional programme in smooth muscle cells to trigger aortic dissection and rupture
复制标题
DOI：
10.1093/eurheartj/ehad534
复制
发表时间：
2023-11-22
影响因子：
39.3
通讯作者：
Ren，Fazheng
中科院分区：
文献类型：
--
作者：
Luo，Yongting;Luo，Junjie;Ren，Fazheng
方法对9例升主动脉置换术患者和5例心脏移植患者的升主动脉进行单细胞RNA测序。通过轨迹推断、功能评分、单细胞调控网络推断和聚类、调控和相互作用分析确定了控制SMCs表型开关的致病靶点，并通过人升主动脉、原发SMCs和β-氨基丙腈单马来酸酯诱导AD模型进行了证实。结果93 397细胞的转录谱显示了一个动态的时间特异性表型转变和激活蛋白-1 （AP-1）复合物的显著升高，积极地促进了合成SMC的扩增。机制上，肿瘤坏死因子信号通过抑制线粒体氧化磷酸化（OXPHOS）增强AP-1转录活性。用OXPHOS增强辅酶Q10或ap -1特异性抑制剂T-5224靶向这条轴，可以阻止表型转变和主动脉变性，同时在β-氨基丙烯单马酸酯诱导的AD模型中，生存率分别提高42.88%（辅酶Q10治疗为58.3%-83.3%）、150.15%（2周T-5224治疗为33.3%-83.3%）和175.38%（3周T-5224治疗为33.3%-91.7%）。结论：在AD进展过程中，人类升主动脉细胞图谱的横断面概要提供了先前未被重视的关于允许主动脉变性的转录程序的见解，强调了通过调节肿瘤坏死因子- oxphos - ap -1轴，抗重构干预作为一种有吸引力的策略来管理时间特异性AD的概念的翻译证明。
MethodsAscending aortas from nine patients undergoing ascending aorta replacement and five individuals undergoing heart transplantation were subjected to single-cell RNA sequencing. The pathogenic targets governing the phenotypic switch of SMCs were identified by trajectory inference, functional scoring, single-cell regulatory network inference and clustering, regulon, and interactome analyses and confirmed using human ascending aortas, primary SMCs, and a β-aminopropionitrile monofumarate-induced AD model.ResultsThe transcriptional profiles of 93 397 cells revealed a dynamic temporal-specific phenotypic transition and marked elevation of the activator protein-1 (AP-1) complex, actively enabling synthetic SMC expansion. Mechanistically, tumour necrosis factor signalling enhanced AP-1 transcriptional activity by dampening mitochondrial oxidative phosphorylation (OXPHOS). Targeting this axis with the OXPHOS enhancer coenzyme Q10 or AP-1-specific inhibitor T-5224 impedes phenotypic transition and aortic degeneration while improving survival by 42.88%(58.3%-83.3% for coenzyme Q10 treatment), 150.15%(33.3%-83.3% for 2-week T-5224), and 175.38%(33.3%-91.7% for 3-week T-5224) in the β-aminopropionitrile monofumarate-induced AD model.ConclusionsThis cross-sectional compendium of cellular atlas of human ascending aortas during AD progression provides previously unappreciated insights into a transcriptional programme permitting aortic degeneration, highlighting a translational proof of concept for an anti-remodelling intervention as an attractive strategy to manage temporal-specific AD by modulating the tumour necrosis factor-OXPHOS-AP-1 axis.