瑞金新知速遞 第322期|李慶雲主任醫師發現線粒體ROS激活NLRP3炎症小體途徑介導間歇性低氧內皮細胞損傷

【Abstract】

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.

【中文摘要】

阻塞性睡眠呼吸暫停（OSA）患者夜間慢性間歇性低氧（CIH）誘發的氧化應激和炎症反應是OSA相關心血管疾病的主要病理生理機制。本研究旨在探索CIH引起的線粒體功能障礙在CIH致內皮細胞損傷中的作用及相關機制。應用CIH細胞和動物模型，研究者發現CIH促進內皮細胞線粒體功能障礙，釋放線粒體ROS誘發內皮損傷，進一步證實CIH暴露激活TXNIP/NLRP3/IL-1β信號通路介導內皮細胞損傷；而應用線粒體靶向抗氧化劑可以抑制TXNIP/NLRP3/IL-1β信號通路的激活，進而緩解內皮細胞損傷。因此，CIH誘發的線粒體功能障礙可能通過調節TXNIP/NLRP3/IL-1β信號通路參與CIH所致內皮損傷機制。