Sun Xiaolei, Jiao Xuefei, Ma Yarong, Liu Yong, Zhang Lei, He Yanzheng, Chen Yunhui
Department of Vascular and Thyroid Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, PR China; State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology), Avenida Wai Long, Taipa, Macau, PR China.
Department of Vascular Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, PR China.
Biochem Biophys Res Commun. 2016 Dec 2;481(1-2):63-70. doi: 10.1016/j.bbrc.2016.11.017. Epub 2016 Nov 8.
Recent research demonstrates that the choline-derived metabolite trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis and cardiovascular risks. The NLRP3 inflammasome responds to exogenous and endogenous danger signals involved in the development of atherosclerosis. Moreover, thioredoxin-interactive protein (TXNIP) activation is a key event linked to NLRP3 inflammasome via reactive oxygen species (ROS). Whether TMAO prime NLRP3 inflammasome via ROS-TXNIP pathway remains unclear. This study observed the expression of TXNIP-NLRP3 inflammasome stimulated by TMAO in human umbilical vein endothelial cells (HUVECs), aiming to elucidate the mechanism by which the TMAO may contribute to inflammation and endothelial dysfunction. Our data showed that TMAO significantly triggered oxidative stress and activated TXNIP-NLRP3 inflammasome whereat inflammatory cytokines interleukin (IL)-1β and IL-18 were released in a dose- and time-dependent manner, but endothelial nitric oxide synthase (eNOS) and production of nitric oxide (NO) were inhibited. Moreover, TMAO-mediated effects were observably reversed by ROS inhibitor N-acetylcysteine (NAC) treatment or siRNA-mediated knockdown TXPIN and NLRP3. Taken together, our results firstly reveal that TMAO induces inflammation and endothelial dysfunction via activating ROS-TXNIP-NLRP3 inflammasome, suggest a likely mechanism for TMAO-dependent enhancement in atherosclerosis and cardiovascular risks.
最近的研究表明，胆碱衍生的代谢物氧化三甲胺（TMAO）水平与动脉粥样硬化和心血管风险密切相关。NLRP3炎性小体对外源性和内源性危险信号作出反应，这些信号参与动脉粥样硬化的发展。此外，硫氧还蛋白相互作用蛋白（TXNIP）的激活是通过活性氧（ROS）与NLRP3炎性小体相关的关键事件。TMAO是否通过ROS-TXNIP途径引发NLRP3炎性小体仍不清楚。本研究观察了TMAO刺激人脐静脉内皮细胞（HUVECs）中TXNIP-NLRP3炎性小体的表达，旨在阐明TMAO可能导致炎症和内皮功能障碍的机制。我们的数据表明，TMAO显著引发氧化应激并激活TXNIP-NLRP3炎性小体，炎性细胞因子白细胞介素（IL）-1β和IL-18以剂量和时间依赖性方式释放，但内皮型一氧化氮合酶（eNOS）和一氧化氮（NO）的产生受到抑制。此外，ROS抑制剂N-乙酰半胱氨酸（NAC）处理或siRNA介导的TXPIN和NLRP3敲低可明显逆转TMAO介导的效应。综上所述，我们的结果首次揭示TMAO通过激活ROS-TXNIP-NLRP3炎性小体诱导炎症和内皮功能障碍，提示了TMAO依赖性增加动脉粥样硬化和心血管风险的可能机制。
