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.

中文翻译：

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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

间歇性缺氧（IH）是阻塞性睡眠呼吸暂停（OSA）中的主要病理生理障碍，已知与心血管疾病独立相关。但是，IH对心脏纤维化和此过程涉及的分子事件的影响尚不清楚。在这里，我们测试了血管紧张素II（Ang II）诱导的心脏纤维化中的IH和与成纤维细胞活化有关的信号传导。IH引发小鼠心脏纤维化并加剧Ang II引起的心脏功能障碍。暴露于IH的小鼠和OSA患者的血浆血小板反应蛋白1（TSP1）含量均上调。而且，在体内和体外结果显示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。机械上，Tyr705处的STAT3磷酸化介导了IH诱导的TSP1表达和成纤维细胞活化。最终，携带Periostin启动子的STAT3抑制剂S3I-201或AAV9驱动靶向Stat3的shRNA的表达，显着减弱了IH和Ang II对小鼠心脏纤维化的协同作用。这项工作表明了OSA相关纤维化性心脏病的潜在治疗策略。