Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis

  1. Qiankun Bao  Is a corresponding author
  2. Bangying Zhang
  3. Ya Suo
  4. Chen Liu
  5. Qian Yang
  6. Kai Zhang
  7. Ming Yuan
  8. Meng Yuan
  9. Yue Zhang
  10. Guangping Li  Is a corresponding author
  1. The Second Hospital of Tianjin Medical University, China
  2. Peking University People's Hospital, China

Abstract

Intermittent hypoxia (IH) is the predominant pathophysiological disturbance in obstructive sleep apnea (OSA), known to be independently associated with cardiovascular diseases. However, the effect of IH on cardiac fibrosis and molecular events involved in this process are unclear. Here, we tested IH in angiotensin II (Ang II)-induced cardiac fibrosis and signaling linked to fibroblast activation. IH triggered cardiac fibrosis and aggravated Ang II-induced cardiac dysfunction in mice. Plasma thrombospondin-1 (TSP1) content was upregulated in both IH-exposed mice and OSA patients. Moreover, both in vivo and in vitro results showed IH-induced cardiac fibroblast activation and increased TSP1 expression in cardiac fibroblasts. Mechanistically, phosphorylation of STAT3 at Tyr705 mediated the IH-induced TSP1 expression and fibroblast activation. Finally, STAT3 inhibitor S3I-201 or AAV9 carrying a periostin promoter driving the expression of shRNA targeting Stat3 significantly attenuated the synergistic effects of IH and Ang II on cardiac fibrosis in mice. This work suggests a potential therapeutic strategy for OSA-related fibrotic heart disease.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1 to 6.

Article and author information

Author details

  1. Qiankun Bao

    Department of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
    For correspondence
    baoqiankun@tmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5221-2780
  2. Bangying Zhang

    Department of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Ya Suo

    Department of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Chen Liu

    Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7120-5626
  5. Qian Yang

    Department of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Kai Zhang

    Department of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Ming Yuan

    Department of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Meng Yuan

    Department of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Yue Zhang

    Department of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Guangping Li

    Department of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
    For correspondence
    tic_tjcardiol@126.com
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Natural Science Foundation of China (81800251)

  • Qiankun Bao

National Natural Science Foundation of China (81570304)

  • Guangping Li

National Natural Science Foundation of China (21800297)

  • Yue Zhang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal procedures were approved and conducted in accordance with the Experimental Animal Administration Committee of Tianjin Medical University (Permit Number: SYXK 2011-0006; SYXK 2016-0012).

Human subjects: Ethical approval was obtained through the institutional ethical review board of Peking University People's Hospital (Permit Number: 2018PHB210-01). The study was conducted in accordance with the Declaration of Helsinki. Written informed consent was taken from all study participants.

Reviewing Editor

  1. Richard P Harvey, Victor Chang Cardiac Research Institute, Australia

Publication history

  1. Received: July 4, 2019
  2. Accepted: January 10, 2020
  3. Accepted Manuscript published: January 14, 2020 (version 1)
  4. Version of Record published: January 30, 2020 (version 2)

Copyright

© 2020, Bao 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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  1. Qiankun Bao
  2. Bangying Zhang
  3. Ya Suo
  4. Chen Liu
  5. Qian Yang
  6. Kai Zhang
  7. Ming Yuan
  8. Meng Yuan
  9. Yue Zhang
  10. Guangping Li
(2020)
Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis
eLife 9:e49923.
https://doi.org/10.7554/eLife.49923

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