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

  1. Abudupataer Mieradilijiang
  2. Shichao Zhu
  3. Shiqiang Yan
  4. Kehua Xu
  5. Jingjing Zhang
  6. Shaman Luo
  7. Wenrui Ma
  8. Md. Fazle Alam
  9. Yuyi Tang
  10. Hui Huang
  11. Nan Chen
  12. Li Wang
  13. Guoquan Yan
  14. Jun Li
  15. Hao Lai
  16. Chunsheng Wang  Is a corresponding author
  17. Kai Zhu  Is a corresponding author
  18. Weijia Zhang  Is a corresponding author
  1. Zhongshan Hospital, Fudan University, China
  2. Zhongshan Hospital, China
  3. Fudan University, China
Research Article
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Cite this article as: eLife 2021;10:e69310 doi: 10.7554/eLife.69310

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

  1. Abudupataer Mieradilijiang

    Zhongshan Hospital, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Shichao Zhu

    Department of Cardiac Surgery, Zhongshan Hospital, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5057-9434
  3. Shiqiang Yan

    Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Kehua Xu

    Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Jingjing Zhang

    Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Shaman Luo

    Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Wenrui Ma

    Zhongshan Hospital, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Md. Fazle Alam

    Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Yuyi Tang

    Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Hui Huang

    Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Nan Chen

    Zhongshan Hospital, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Li Wang

    Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Guoquan Yan

    Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Jun Li

    Zhongshan Hospital, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Hao Lai

    Zhongshan Hospital, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  16. Chunsheng Wang

    Zhongshan Hospital, Fudan University, Shanghai, China
    For correspondence
    wangchunsheng@fudan.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  17. Kai Zhu

    Zhongshan Hospital, Fudan University, Shanghai, China
    For correspondence
    zhu.kai1@zs-hospital.sh.cn
    Competing interests
    The authors declare that no competing interests exist.
  18. Weijia Zhang

    Fudan University, Shanghai, China
    For correspondence
    weijiazhang@fudan.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6928-0416

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.

Reviewing Editor

  1. Simon C Johnson, University of Washington, United States

Publication history

  1. Received: April 11, 2021
  2. Preprint posted: July 9, 2021 (view preprint)
  3. Accepted: August 18, 2021
  4. Accepted Manuscript published: September 6, 2021 (version 1)
  5. Version of Record published: September 17, 2021 (version 2)

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.

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    Background:

    Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anticancer agent tamoxifen has synergistic anti-cryptococcal activity with amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential.

    Methods:

    Open label randomized controlled trial. Participants received standard care – amphotericin combined with fluconazole for the first 2 weeks – or standard care plus tamoxifen 300 mg/day. The primary end point was Early Fungicidal Activity (EFA) – the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031.

    Results:

    Fifty patients were enrolled (median age 34 years, 35 male). Tamoxifen had no effect on EFA (−0.48log10 colony-forming units/mL/CSF control arm versus −0.49 tamoxifen arm, difference −0.005log10CFU/ml/day, 95% CI: −0.16, 0.15, p=0.95). Tamoxifen caused QTc prolongation.

    Conclusions:

    High-dose tamoxifen does not increase the clearance rate of Cryptococcus from CSF. Novel, affordable therapies are needed.

    Funding:

    The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA.

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