Department of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, No. 10 Tianxiu Road, Haidian District, China Agricultural University, Beijing 100193, China.
Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, No. 2 Anzhen Road, Chaoyang District, Beijing 100029, China.
Eur Heart J. 2024 Jan 27;45(4):287-305. doi: 10.1093/eurheartj/ehad534.
Stanford type A aortic dissection (AD) is a degenerative aortic remodelling disease marked by an exceedingly high mortality without effective pharmacologic therapies. Smooth muscle cells (SMCs) lining tunica media adopt a range of states, and their transformation from contractile to synthetic phenotypes fundamentally triggers AD. However, the underlying pathomechanisms governing this population shift and subsequent AD, particularly at distinct disease temporal stages, remain elusive.
Ascending 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.
The 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.
This 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.
斯坦福 A 型主动脉夹层（AD）是一种退行性主动脉重塑疾病，其死亡率极高，目前尚无有效的药物治疗方法。中层平滑肌细胞（SMCs）呈现多种状态，其从收缩型向合成型表型的转变是 AD 的根本触发因素。然而，调控这种细胞群体转变及随后 AD 的潜在病理机制，尤其是在不同疾病的时间阶段，仍然难以捉摸。
对 9 例升主动脉置换术和 5 例心脏移植术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、调控子和互作网络分析，确定调控 SMC 表型转换的致病靶点，并通过人升主动脉、原代 SMC 和 β-氨基丙腈单琥珀酸诱导的 AD 模型进行验证。
93397 个细胞的转录谱揭示了一种动态的、具有时间特异性的表型转变，并显著上调了激活蛋白-1（AP-1）复合物，积极促进合成型 SMC 的扩增。在机制上，肿瘤坏死因子信号通过抑制线粒体氧化磷酸化（OXPHOS）增强了 AP-1 的转录活性。用 OXPHOS 增强剂辅酶 Q10 或 AP-1 特异性抑制剂 T-5224 靶向该轴，可阻止表型转变和主动脉退化，同时提高β-氨基丙腈单琥珀酸诱导的 AD 模型的存活率，分别提高 42.88%（辅酶 Q10 治疗组为 58.3%-83.3%）、150.15%（T-5224 治疗组为 2 周时 33.3%-83.3%）和 175.38%（T-5224 治疗组为 3 周时 33.3%-91.7%）。
本研究对人类升主动脉 AD 进展过程中的细胞图谱进行了横断面汇编，为主动脉退化提供了以前未被重视的转录谱见解，强调了一种抗重塑干预的转化概念，即通过调节肿瘤坏死因子-OXPHOS-AP-1 轴来管理具有时间特异性的 AD，这是一种有吸引力的策略。
