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

• Published in: eLife Vol. 10
• Main Authors: Abudupataer, Mieradilijiang, Zhu, Shichao, Yan, Shiqiang, Xu, Kehua, Zhang, Jingjing, Luo, Shaman, Ma, Wenrui, Alam, Md Fazle, Tang, Yuyi, Huang, Hui, Chen, Nan, Wang, Li, Yan, Guoquan, Li, Jun, Lai, Hao, Wang, Chunsheng, Zhu, Kai, Zhang, Weijia
• Format: Journal Article
• Language: English
• Published: Cambridge eLife Sciences Publications Ltd 06-09-2021; eLife Sciences Publications, Ltd
• Subjects: Antibodies; Aorta; Aortic aneurysms; Aortic valve; bicuspid aortic valve; Cardiovascular diseases; Chemical compounds; Coronary vessels; Drug screening; human aortic; Leflunomide; Medicine; Membranes; Microfluidics; Mitochondria; mitochondrial dynamics; Muscle contraction; Notch1 protein; organ-on-a-chip; Pathogenesis; Pharmaceuticals; Phenotypes; Polymethyl methacrylate; Proteomics; Smooth muscle; smooth muscle cells; Therapeutic applications; thoracic aortic aneurysm; Thorax
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.69310

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.
To function properly, the heart must remain a one-way system, pumping out oxygenated blood into the aorta – the largest artery in the body – so it can be distributed across the organism. The aortic valve, which sits at the entrance of the aorta, is a key component of this system. Its three flaps (or ‘cusps’) are pushed open when the blood exits the heart, and they shut tightly so it does not flow back in the incorrect direction.
Nearly 1.4% of people around the world are born with ‘bicuspid’ aortic valves that only have two flaps. These valves may harden or become leaky, forcing the heart to work harder. This defect is also associated with bulges on the aorta which progressively weaken the artery, sometimes causing it to rupture.
Open-heart surgery is currently the only way to treat these bulges (or ‘aneurysms’), as no drug exists that could slow down disease progression. This is partly because the biological processes involved in the aneurysms worsening and bursting open is unclear.
Recent studies have highlighted that many individuals with bicuspid aortic valves also have lower levels of a protein known as NOTCH1, which plays a key signalling role for cells. Problems in the mitochondria – the structures that power up a cell – are also observed. However, it is not known how these findings are connected or linked with the aneurysms developing.
To answer this question, Abudupataer et al. analyzed the proteins present in diseased and healthy aortic muscle cells, confirming a lower production of NOTCH1 and impaired mitochondria in diseased tissues. They also created an ‘aorta-on-a-chip’ model where aortic muscle cells were grown in the laboratory under conditions resembling those found in the body – including the rhythmic strain that the aorta is under because of the heart beating. Abudupataer et al. then reduced NOTCH1 levels in healthy samples, which made the muscle tissue less able to contract and reduced the activity of the mitochondria. Applying drugs that tweak mitochondrial activity helped tissues from patients with bicuspid aortic valves to work better.
These compounds could potentially benefit individuals with deficient aortic valves, but experiments in animals and clinical trials would be needed first to confirm the results and assess safety. The aorta-on-a-chip model developed by Abudupataer et al. also provides a platform to screen for drugs and examine the molecular mechanisms at play in aortic diseases.