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

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...

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Autores principales: Bao, Qiankun, Zhang, Bangying, Suo, Ya, Liu, Chen, Yang, Qian, Zhang, Kai, Yuan, Ming, Yuan, Meng, Zhang, Yue, Li, Guangping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992386/
https://www.ncbi.nlm.nih.gov/pubmed/31934850
http://dx.doi.org/10.7554/eLife.49923
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author Bao, Qiankun
Zhang, Bangying
Suo, Ya
Liu, Chen
Yang, Qian
Zhang, Kai
Yuan, Ming
Yuan, Meng
Zhang, Yue
Li, Guangping
author_facet Bao, Qiankun
Zhang, Bangying
Suo, Ya
Liu, Chen
Yang, Qian
Zhang, Kai
Yuan, Ming
Yuan, Meng
Zhang, Yue
Li, Guangping
author_sort Bao, Qiankun
collection PubMed
description 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.
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spelling pubmed-69923862020-01-31 Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis Bao, Qiankun Zhang, Bangying Suo, Ya Liu, Chen Yang, Qian Zhang, Kai Yuan, Ming Yuan, Meng Zhang, Yue Li, Guangping eLife Human Biology and Medicine 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. eLife Sciences Publications, Ltd 2020-01-14 /pmc/articles/PMC6992386/ /pubmed/31934850 http://dx.doi.org/10.7554/eLife.49923 Text en © 2020, Bao et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Human Biology and Medicine
Bao, Qiankun
Zhang, Bangying
Suo, Ya
Liu, Chen
Yang, Qian
Zhang, Kai
Yuan, Ming
Yuan, Meng
Zhang, Yue
Li, Guangping
Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis
title Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis
title_full Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis
title_fullStr Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis
title_full_unstemmed Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis
title_short Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis
title_sort intermittent hypoxia mediated by tsp1 dependent on stat3 induces cardiac fibroblast activation and cardiac fibrosis
topic Human Biology and Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992386/
https://www.ncbi.nlm.nih.gov/pubmed/31934850
http://dx.doi.org/10.7554/eLife.49923
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