Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis
- The Second Hospital of Tianjin Medical University, China
- 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
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.
Reviewing Editor
- Richard P Harvey, Victor Chang Cardiac Research Institute, Australia
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.
Version history
- Received: July 4, 2019
- Accepted: January 10, 2020
- Accepted Manuscript published: January 14, 2020 (version 1)
- 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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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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