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

被引:51
作者
Bao, Qiankun [1 ]
Zhang, Bangying [1 ]
Suo, Ya [1 ]
Liu, Chen [2 ]
Yang, Qian [1 ]
Zhang, Kai [1 ]
Yuan, Ming [1 ]
Yuan, Meng [1 ]
Zhang, Yue [1 ]
Li, Guangping [1 ]
机构
[1] Tianjin Med Univ, Hosp 2, Tianjin Inst Cardiol, Dept Cardiol,Tianjin Key Lab Ion Mol Funct Cardio, Tianjin, Peoples R China
[2] Peking Univ, Peoples Hosp, Dept Clin Lab, Beijing, Peoples R China
基金
中国国家自然科学基金;
关键词
OBSTRUCTIVE SLEEP-APNEA; TGF-BETA; CARDIOVASCULAR-DISEASE; OXIDATIVE STRESS; THROMBOSPONDIN-1; GROWTH; MECHANISMS; ANGIOGENESIS; ASSOCIATION; DYSFUNCTION;
D O I
10.7554/eLife.49923
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
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页数:20
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