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

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.

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

  • 1,878
    views
  • 350
    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)

  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
  17. Kai Zhu
  18. Weijia Zhang
(2021)
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

Share this article

https://doi.org/10.7554/eLife.69310

Further reading

    1. Medicine
    Yanling Huang, Haocong Mo ... Geyang Xu
    Research Article

    Glucagon-like peptide 1 (GLP-1) is a gut-derived hormone secreted by intestinal L cells and vital for postprandial glycemic control. As open-type enteroendocrine cells, whether L cells can sense mechanical stimuli caused by chyme and thus regulate GLP-1 synthesis and secretion is unexplored. Molecular biology techniques revealed the expression of Piezo1 in intestinal L cells. Its level varied in different energy status and correlates with blood glucose and GLP-1 levels. Mice with L cell-specific loss of Piezo1 (Piezo1 IntL-CKO) exhibited impaired glucose tolerance, increased body weight, reduced GLP-1 production and decreased CaMKKβ/CaMKIV-mTORC1 signaling pathway under normal chow diet or high-fat diet. Activation of the intestinal Piezo1 by its agonist Yoda1 or intestinal bead implantation increased the synthesis and secretion of GLP-1, thus alleviated glucose intolerance in diet-induced-diabetic mice. Overexpression of Piezo1, Yoda1 treatment or stretching stimulated GLP-1 production and CaMKKβ/CaMKIV-mTORC1 signaling pathway, which could be abolished by knockdown or blockage of Piezo1 in primary cultured mouse L cells and STC-1 cells. These experimental results suggest a previously unknown regulatory mechanism for GLP-1 production in L cells, which could offer new insights into diabetes treatments.

    1. Medicine
    Pinanong Na-Phatthalung, Shumin Sun ... Fudi Wang
    Research Article

    The zinc transporter Slc30a1 plays an essential role in maintaining cellular zinc homeostasis. Despite this, its functional role in macrophages remains largely unknown. Here, we examine the function of Slc30a1 in host defense using mice models infected with an attenuated stain of Salmonella enterica Typhimurium and primary macrophages infected with the attenuated Salmonella. Bulk transcriptome sequencing in primary macrophages identifies Slc30a1 as a candidate in response to Salmonella infection. Whole-mount immunofluorescence and confocal microscopy imaging of primary macrophage and spleen from Salmonella-infected Slc30a1flag-EGFP mice demonstrate Slc30a1 expression is increased in infected macrophages with localization at the plasma membrane and in the cytosol. Lyz2-Cre-driven Slc30a1 conditional knockout mice (Slc30a1fl/fl;Lyz2-Cre) exhibit increased susceptibility to Salmonella infection compared to control littermates. We demonstrate that Slc30a1-deficient macrophages are defective in intracellular killing, which correlated with reduced activation of nuclear factor kappa B and reduction in nitric oxide (NO) production. Notably, the model exhibits intracellular zinc accumulation, demonstrating that Slc30a1 is required for zinc export. We thus conclude that zinc export enables the efficient NO-mediated antibacterial activity of macrophages to control invading Salmonella.