Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis
Intermittent hypoxia mediated by TSP1 dependent on STAT3 induces cardiac fibroblast activation and cardiac fibrosis
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TSP1依赖STAT3介导的间歇性缺氧诱导心脏成纤维细胞活化和心脏纤维化
DOI：
10.7554/elife.49923
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发表时间：
2020-01-14
期刊：
影响因子：
7.7
通讯作者：
Li, Guangping
中科院分区：
文献类型：
--
作者：
Bao, Qiankun;Zhang, Bangying;Li, Guangping
间歇性缺氧（IH）是阻塞性睡眠呼吸暂停（OSA）的主要病理生理障碍，已知与心血管疾病独立相关。然而，IH对心脏纤维化的影响和参与这一过程的分子事件尚不清楚。在这里，我们测试了IH在血管紧张素II （Ang II）诱导的心脏纤维化和与成纤维细胞激活相关的信号传导中的作用。IH引发小鼠心脏纤维化，加重Angⅱ诱导的心功能障碍。ih暴露小鼠和OSA患者血浆血栓反应蛋白-1 （TSP1）含量均上调。此外，体内和体外结果均显示ih诱导的心脏成纤维细胞活化和心脏成纤维细胞中TSP1表达增加。在机制上，STAT3在Tyr705位点的磷酸化介导了ih诱导的TSP1表达和成纤维细胞激活。最后，STAT3抑制剂sgi -201或携带骨膜蛋白启动子驱动靶向STAT3的shRNA表达的AAV9显著减弱IH和Ang II对小鼠心脏纤维化的协同作用。这项工作为osa相关的纤维化心脏病提供了一种潜在的治疗策略。
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.