Aorta smooth muscle-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease
- Zhongshan Hospital, Fudan University, China
- Zhongshan Hospital, China
- Fudan University, China
Abstract
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&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.
Data availability
All the data associated with this study are included in the paper or Supplementary Files. The mass spectrometry proteomics data, including raw data from the mass spectrometry runs, have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD026303. The analyzed data are reported in Figure1 and Figure 1-source data 2-4.
Article and author information
Author details
Funding
National Natural Science Foundation of China (82070482,81772007,21734003,and 51927805)
- Weijia Zhang
National Key Research and Development Program of China (2018YFC1005002)
- Weijia Zhang
National Natural Science Foundation of China (81771971)
- Kai Zhu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Written informed consent was obtained from all patients before participation. Human aortic specimens were utilized under approvals of Zhongshan Hospital, Fudan University Ethics Committee (NO. B2020-158) in accordance with the Declaration of Helsinki.
Copyright
© 2021, Mieradilijiang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,998
- views
-
- 375
- downloads
-
- 28
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Aorta smooth muscle-on-a-chip reveals impaired mitochondrial dynamics as a therapeutic target for aortic aneurysm in bicuspid aortic valve disease
eLife 10:e69310.
https://doi.org/10.7554/eLife.69310
Further reading
-
- Medicine
- Microbiology and Infectious Disease
Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are a barrier to cure efforts. Early antiretroviral therapy (ART) enables post-treatment viral control in some cases, but mechanisms remain unclear. We hypothesised that ART initiated before peak viremia impacts HIV-1 subtype C reservoirs. We studied 35 women at high risk of infection from Durban, South Africa, identified with hyperacute HIV by twice-weekly HIV-RNA testing. Participants included 11 starting ART at a median of 456 (297–1203) days post-onset of viremia (DPOV) and 24 at 1 (1–3) DPOV. Peripheral blood mononuclear cells (PBMCs) were used to measured total HIV-1 DNA by droplet digital PCR (ddPCR) and sequence viral reservoir genomes by full-length proviral sequencing (FLIP-seq). ART during hyperacute infection blunted peak viremia (p<0.0001), but contemporaneous total HIV-1 DNA did not differ (p=0.104). Over 1 year, a decline of total HIV-1 DNA was observed in early treated persons (p=0.0004), but not late treated. Among 697 viral genome sequences, the proviral genetic landscape differed between untreated, late treated, and early treated groups. Intact genomes after 1 year were higher in untreated (31%) versus late treated (14%) and early treated (0%). Treatment in both late and early infection caused more rapid decay of intact (13% and 51% per month) versus defective (2% and 35%) viral genomes. However, intact genomes persisted 1 year post chronic treatment but were undetectable with early ART. Early ART also reduced phylogenetic diversity of intact genomes and limited cytotoxic T lymphocyte immune escape variants in the reservoir. Overall, ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding but was associated with rapid intact viral genome decay, reduced genetic complexity, and limited immune escape, which may accelerate reservoir clearance in combination with other interventional strategies.
-
- Cancer Biology
- Medicine
A doctoral-level internship program was developed at the University of North Carolina at Chapel Hill with the intent to create customizable experiential learning opportunities for biomedical trainees to support career exploration, preparation, and transition into their postgraduate professional roles. We report the outcomes of this program over a 5-year period. During that 5-year period, 123 internships took place at over 70 partner sites, representing at least 20 academic, for-profit, and non-profit career paths in the life sciences. A major goal of the program was to enhance trainees’ skill development and expertise in careers of interest. The benefits of the internship program for interns, host/employer, and supervisor/principal investigator were assessed using a mixed-methods approach, including surveys with closed- and open-ended responses as well as focus group interviews. Balancing stakeholder interests is key to creating a sustainable program with widespread support; hence, the level of support from internship hosts and faculty members were the key metrics analyzed throughout. We hypothesized that once a successful internship program was implemented, faculty culture might shift to be more accepting of internships; indeed, the data quantifying faculty attitudes support this. Furthermore, host motivation and performance expectations of interns were compared with results achieved, and this data revealed both expected and surprising benefits to hosts. Data suggests a myriad of benefits for each stakeholder group, and themes are cataloged and discussed. Program outcomes, evaluation data, policies, resources, and best practices developed through the implementation of this program are shared to provide resources that facilitate the creation of similar internship programs at other institutions. Program development was initially spurred by National Institutes of Health pilot funding, thereafter, successfully transitioning from a grant-supported model, to an institutionally supported funding model to achieve long-term programmatic sustainability.
