TY - JOUR TI - Aorta smooth muscle-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease AU - Abudupataer, Mieradilijiang AU - Zhu, Shichao AU - Yan, Shiqiang AU - Xu, Kehua AU - Zhang, Jingjing AU - Luo, Shaman AU - Ma, Wenrui AU - Alam, Md Fazle AU - Tang, Yuyi AU - Huang, Hui AU - Chen, Nan AU - Wang, Li AU - Yan, Guoquan AU - Li, Jun AU - Lai, Hao AU - Wang, Chunsheng AU - Zhu, Kai AU - Zhang, Weijia A2 - Johnson, Simon C A2 - Bhargava, Balram VL - 10 PY - 2021 DA - 2021/09/06 SP - e69310 C1 - eLife 2021;10:e69310 DO - 10.7554/eLife.69310 UR - https://doi.org/10.7554/eLife.69310 AB - Background:. Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. Insufficiency of NOTCH1 expression is highly related to BAV-TAA, but the underlying mechanism remains to be clarified. Methods:. A comparative proteomics analysis was used to explore the biological differences between non-diseased and BAV-TAA aortic tissues. A microfluidics-based aorta smooth muscle-on-a-chip model was constructed to evaluate the effect of NOTCH1 deficiency on contractile phenotype and mitochondrial dynamics of human aortic smooth muscle cells (HAoSMCs). Results:. Protein analyses of human aortic tissues showed the insufficient expression of NOTCH1 and impaired mitochondrial dynamics in BAV-TAA. HAoSMCs with NOTCH1-knockdown exhibited reduced contractile phenotype and were accompanied by attenuated mitochondrial fusion. Furthermore, we identified that mitochondrial fusion activators (leflunomide and teriflunomide) or mitochondrial fission inhibitor (Mdivi-1) partially rescued the disorders of mitochondrial dynamics in HAoSMCs derived from BAV-TAA patients. Conclusions:. The aorta smooth muscle-on-a-chip model simulates the human pathophysiological parameters of aorta biomechanics and provides a platform for molecular mechanism studies of aortic disease and related drug screening. This aorta smooth muscle-on-a-chip model and human tissue proteomic analysis revealed that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA. Funding:. National Key R and D Program of China, National Natural Science Foundation of China, Shanghai Municipal Science and Technology Major Project, Shanghai Science and Technology Commission, and Shanghai Municipal Education Commission. KW - organ-on-a-chip KW - thoracic aortic aneurysm KW - bicuspid aortic valve KW - mitochondrial dynamics KW - human aortic KW - smooth muscle cells JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -