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

Abstract

BackgroundBicuspid 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.MethodsA comparative proteomics analysis was used to explore the biological differences between non-diseased and BAV-TAA aortic tissues. A microfluidics-based aorta-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).ResultsProtein 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.ConclusionsThe aorta-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-on-a-chip model and human tissue proteomic analysis revealed that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA.FundingNational Key R&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.

A hiPSC-derived lineage-specific vascular smooth muscle cell-on-a-chip identifies aortic heterogeneity across segments

“…In contrast to traditional cell culture techniques, which often fail to mimic the physiological environment of cultured cells, recent studies have shown that microfluidic chip technology can mirror natural cellular development processes to yield more accurate physiological characteristics. 23 Although animal models are widely used to study AA, species differences, high costs, and time limitations hinder their applicability in pharmaceutical drug screening. Our hiPSC-SMC-based organ-on-a-chip may be a suitable complement to animal models for mechanistic research and drug screening for AA.…”

“…We have described micro-physiological model fabrication and mechanical stimulation parameters in detail in our previous study. 23 To replicate different strains on the human aortic wall, we applied 7.15 ± 0.45% strain induced by a vacuum pressure of 10 kPa as a relatively low strain and 17.25 ± 0.95% strain induced by a vacuum pressure of 15 kPa as a relatively high strain. The liquid channel part of the LM-SMC, NC-SMC, or PM-SMC chips was connected in series as an entire lineagespecific SMC-on-a-chip, driven by a liquid pump, and the culture medium maintained uninterrupted circulation.…”

“…3A). 23 The hiPSC-SMCs were cultured on PDMS membranes in the middle cell culture chamber (Fig. 3B).…”

“…The cell phenotype and function were found to be similar to their native status in vivo. 23 The pathogenesis, therapeutic targets, and drug responses of aortopathy could be investigated using the organ-on-a-chip approach.…”

Mitochondrial dynamics in neurological diseases: a narrative review

“…The ability of leflunomide to improve mitochondrial dynamics has been used to treat pancreatic cancer and mitral aortic valve disease. Enhanced mitochondrial fission inhibits metastasis in triple-negative breast cancer, and leflunomide has been shown to counteract this inhibitory effect (81)(82)(83).…”