Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
Shiqiang Yan
Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China
Kehua Xu
Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China
Jingjing Zhang
Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China
Shaman Luo
Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China; The State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, China
Wenrui Ma
Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
Md Fazle Alam
Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China; The State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, China
Yuyi Tang
Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China
Hui Huang
Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China
Nan Chen
Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
Li Wang
Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China
Guoquan Yan
Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China
Jun Li
Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China
Hao Lai
Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
Chunsheng Wang
Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China; The State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, China
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.
