Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis
| Autor: | Ya Suo, Bangying Zhang, Guangping Li, Yue Zhang, Qiankun Bao, Meng Yuan, Kai Zhang, Ming Yuan, Chen Liu, Qian Yang |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Mouse Cardiac fibrosis cardiac fibrosis 030204 cardiovascular system & hematology Thrombospondin 1 STAT3 TSP1 Small hairpin RNA Mice cardiac fibroblast activation 0302 clinical medicine Biology (General) Phosphorylation RNA Small Interfering Hypoxia Promoter Regions Genetic biology Basic Helix-Loop-Helix Leucine Zipper Transcription Factors General Neuroscience Heart Intermittent hypoxia General Medicine medicine.anatomical_structure Echocardiography cardiovascular system Medicine Signal Transduction Research Article Human STAT3 Transcription Factor QH301-705.5 Science intermittent hypoxia Periostin General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Downregulation and upregulation medicine Animals Humans Gene Silencing Human Biology and Medicine Fibroblast General Immunology and Microbiology business.industry Myocardium Fibroblasts medicine.disease Fibrosis Angiotensin II Mice Inbred C57BL 030104 developmental biology Gene Expression Regulation biology.protein Cancer research Tyrosine business |
| Zdroj: | eLife eLife, Vol 9 (2020) |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.49923 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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