Aorta smooth muscle-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease

Background: Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and frequently associated with development of thoracic aneurysm (TAA). There no effective strategy to intervene TAA progression due an incomplete understanding pathogenesis. Insufficiency NOTCH1 expression highly related BAV-TAA, but underlying mechanism remains be clarified. Methods: A comparative proteomics analysis was used explore biological differences between non-diseased BAV-TAA tissues. microfluidics-based aorta smooth muscle-on-a-chip model constructed evaluate effect deficiency on contractile phenotype mitochondrial dynamics human muscle cells (HAoSMCs). Results: Protein analyses tissues showed insufficient impaired BAV-TAA. HAoSMCs NOTCH1-knockdown exhibited reduced were accompanied by attenuated fusion. Furthermore, we identified that fusion activators (leflunomide teriflunomide) or fission inhibitor (Mdivi-1) partially rescued disorders derived from patients. Conclusions: The simulates pathophysiological parameters biomechanics provides a platform for molecular studies drug screening. This tissue proteomic revealed could potential therapeutic target Funding: National Key R D Program China, Natural Science Foundation Shanghai Municipal Technology Major Project, Commission, Education Commission.