Gao Qiannan, Bao Minghui, Tan Jiangshan, Zhang Haizeng, Fan Luyun, Zhou Yiran, Mao Liyan, Huang Chengjun, Zhang Weili, Geng Bin, Fan Xiaohan, Cai Jun, Chen Zhenzhen
Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.
Fuwai Hospital, National Center for Cardiovascular Diseases of China, CAMS and PUMC, Beijing, China.
Hypertens Res. 2025 Aug 7. doi: 10.1038/s41440-025-02315-8.
Thoracic aortic dissection (TAD) is a leading cause of sudden cardiovascular death. Although a limited number of copy number variations (CNVs) have been reported in small cohorts of patients with hereditary TAD or sporadic aortic dissection, a comprehensive investigation and functional validation of CNVs in sporadic TAD using large-scale whole genome sequencing (WGS) data remain lacking. To address this gap, we conducted whole genome sequencing in two independent case-control studies, involving 257 patients with sporadic TAD and 132 controls. We generated gene knockout mice to explore the role of the target gene in TAD progression in vivo. Additionally, RNA-seq analysis and molecular biology experiments were performed in vitro to elucidate the underlying mechanisms. In the discovery and validation cohorts, we identified four CNVs genes (DSCAM, APP, LINC00907, PROCR) potentially pivotal in the pathogenesis of TAD. Among these, only APP displayed reduced expression in the aortas of TAD patients compared to controls. Deletion of APP exacerbated elastic fiber fragmentation and promoted TAD formation in both β-aminopropionitrile (BAPN)-induced and PCSK9/AngII-induced TAD models. In vitro, the loss of APP facilitated vascular smooth muscle cells (VSMCs) apoptosis and the switch to a secretory phenotype. Our study is the first to report novel CNVs of APP in TAD, demonstrating that APP deficiency accelerates the initiation and progression of TAD. These findings suggest that APP represents a promising therapeutic target and a potential genetic risk factor for TAD.
胸主动脉夹层（TAD）是心血管猝死的主要原因。尽管在遗传性TAD或散发性主动脉夹层患者的小队列中已报道了数量有限的拷贝数变异（CNV），但利用大规模全基因组测序（WGS）数据对散发性TAD中的CNV进行全面调查和功能验证仍然缺乏。为了填补这一空白，我们在两项独立的病例对照研究中进行了全基因组测序，涉及257例散发性TAD患者和132例对照。我们生成了基因敲除小鼠，以探索靶基因在TAD体内进展中的作用。此外，还进行了RNA测序分析和体外分子生物学实验，以阐明潜在机制。在发现和验证队列中，我们鉴定出四个在TAD发病机制中可能起关键作用的CNV基因（DSCAM、APP、LINC00907、PROCR）。其中，与对照组相比，只有APP在TAD患者的主动脉中表达降低。在β-氨基丙腈（BAPN）诱导和PCSK9/AngII诱导的TAD模型中，APP的缺失加剧了弹性纤维断裂并促进了TAD的形成。在体外，APP的缺失促进了血管平滑肌细胞（VSMC）凋亡并使其转变为分泌表型。我们的研究首次报道了TAD中APP的新CNV，表明APP缺乏会加速TAD的起始和进展。这些发现表明，APP是一个有前景的治疗靶点和TAD的潜在遗传风险因素。
