Dimethyl Fumarate Is Repurposed to Ameliorate Aortic Aneurysm and Dissection in Mice

Abstract

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 CaCl₂ 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.

Keywords: Aortic aneurysm; Aortic dissection; Collagen assembly; Dimethyl fumarate; Focal adhesion.