Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Institute of Respiratory Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 200 025, China.
Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; Institute of Respiratory Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 200 025, China.
Free Radic Biol Med. 2021 Mar;165:401-410. doi: 10.1016/j.freeradbiomed.2021.01.053. Epub 2021 Feb 9.
Oxidative stress and inflammation induced by chronic intermittent hypoxia (CIH) are trigger factors of cardiovascular diseases in patients with obstructive sleep apnea (OSA). This study aimed to investigate the role of CIH-induced mitochondrial dysfunction in vascular endothelial injury both in vivo and in vitro. Human umbilical vein endothelial cells and Sprague Dawley rats were exposed to CIH. CIH promoted the production of intracellular reactive oxygen species, caused mitochondrial dysfunction, and induced cell apoptosis in human umbilical vein endothelial cells. RNA-Seq analysis revealed that the NOD-like receptor signaling pathway was involved in endothelial injury induced by CIH. TXNIP/NLRP3/IL-1β pathway was found to be upregulated by CIH. Knock-down of TNXIP rescued the endothelial cells from CIH-induced apoptosis, indicating that activation of the TXNIP/NLRP3/IL-1β pathway mediated the CIH-induced endothelial apoptosis. Administration of the mitochondria-targeted antioxidant mito-TEMPO improved mitochondrial function and suppressed upregulation of the TXNIP/NLRP3/IL-1β pathway, thereby alleviating CIH-induced endothelial apoptosis. In vivo experiments confirmed the results, where mito-TEMPO was found to ameliorate endothelial injury in rat aortas exposed to CIH. The results imply that CIH-induced mitochondrial dysfunction mediates endothelial injury implication of TXNIP/NLRP3/IL-1β signaling pathway.
慢性间歇性低氧（CIH）引起的氧化应激和炎症是阻塞性睡眠呼吸暂停（OSA）患者心血管疾病的触发因素。本研究旨在探讨 CIH 诱导的线粒体功能障碍在血管内皮损伤中的作用，既包括在体实验又包括体外实验。将人脐静脉内皮细胞和 Sprague Dawley 大鼠暴露于 CIH 中。CIH 促进了细胞内活性氧的产生，导致线粒体功能障碍，并诱导人脐静脉内皮细胞凋亡。RNA-Seq 分析显示，NOD 样受体信号通路参与了 CIH 诱导的内皮损伤。发现 CIH 上调了 TXNIP/NLRP3/IL-1β 通路。敲低 TNXIP 可挽救内皮细胞免受 CIH 诱导的凋亡，表明 TXNIP/NLRP3/IL-1β 通路的激活介导了 CIH 诱导的内皮细胞凋亡。线粒体靶向抗氧化剂 mito-TEMPO 的给药改善了线粒体功能，并抑制了 TXNIP/NLRP3/IL-1β 通路的上调，从而减轻了 CIH 诱导的内皮细胞凋亡。体内实验证实了这一结果，发现 mito-TEMPO 可改善 CIH 暴露的大鼠主动脉内皮损伤。结果表明，CIH 诱导的线粒体功能障碍介导了 TXNIP/NLRP3/IL-1β 信号通路的内皮损伤。
