Wang Xuan, Kuang Jin, Li Xiao-Tian, Hu Xi, Liu Yu-Hang, Hu Chang-Ping, Wang Mi, Wang Qing, Zhang Zheng
Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, Hunan, China.
Department of the Interventional Radiology & Vascular Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, Hunan, China.
Eur J Pharmacol. 2025 Feb 5;988:177215. doi: 10.1016/j.ejphar.2024.177215. Epub 2024 Dec 18.
Aortic aneurysm and dissection pose fatal threats but no effective drug therapies are available. Previous work has been directed to reduce risk factors or target key pathological events, but none of the translational efforts succeeds. Here, we attempt to repurpose dimethyl fumarate (DMF), an FDA-approved immunomodulatory drug for multiple sclerosis, for the treatment of aortic aneurysm and dissection. In three preclinical mouse models of abdominal aortic aneurysm (porcine pancreatic elastase perfusion or CaCl incubation) and thoracic aortic aneurysm and dissection (β-Aminopropionitrile feeding), DMF invariably protected mice from aneurysm growth, aortic dissection, rupture and death. Histological H&E and EVG staining demonstrated aortic architecture-preserving effects of DMF. Through transcriptome profiling and the connectivity map (CMap), we showed that DMF restored SRC-FAK signaling in aortic smooth muscle cells and increased collagen I turnover in the tunica media. Our work suggests the potential of DMF being repurposed for aortic aneurysm and dissection, and highlights the importance of SRC-FAK signaling in aortic homeostasis.
主动脉瘤和主动脉夹层构成致命威胁，但目前尚无有效的药物治疗方法。先前的研究致力于降低风险因素或针对关键病理事件，但所有转化研究均未成功。在此，我们尝试将已获美国食品药品监督管理局（FDA）批准用于治疗多发性硬化症的免疫调节药物富马酸二甲酯（DMF）重新用于治疗主动脉瘤和主动脉夹层。在三种腹主动脉瘤的临床前小鼠模型（猪胰弹性蛋白酶灌注或氯化钙孵育）以及胸主动脉瘤和主动脉夹层（β-氨基丙腈喂养）中，DMF始终能保护小鼠免受动脉瘤生长、主动脉夹层、破裂和死亡的影响。组织学苏木精-伊红（H&E）和弹性纤维-van Gieson（EVG）染色显示了DMF对主动脉结构的保护作用。通过转录组分析和连接图谱（CMap），我们发现DMF可恢复主动脉平滑肌细胞中的Src-黏着斑激酶（FAK）信号，并增加中膜中I型胶原蛋白的更新。我们的研究表明DMF重新用于治疗主动脉瘤和主动脉夹层的潜力，并强调了Src-FAK信号在主动脉稳态中的重要性。
