Trimethylamine-N-Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3-SOD2-mtROS Signaling Pathway.
Trimethylamine-N-Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3-SOD2-mtROS Signaling Pathway.
复制标题
三甲胺-N-氧化物通过 SIRT3-SOD2-mtROS 信号通路激活 NLRP3 炎症小体诱导血管炎症
DOI：
10.1161/jaha.117.006347
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发表时间：
2017-09-04
影响因子：
5.4
通讯作者：
Mi MT
中科院分区：
文献类型：
--
作者：
Chen ML;Zhu XH;Ran L;Lang HD;Yi L;Mi MT
三甲胺-N-氧化物(TMAO)最近被认为是一种新的独立危险因素，可通过诱导血管炎症来促进动脉粥样硬化。然而，确切的机制目前尚不清楚。研究证实了核苷酸结合的寡聚化结构域样受体家族3(NLRP3)炎症体在血管炎症发病机制中的核心作用。在这里，我们研究了NLRP3炎症体在体外和体内TMAO诱导的血管炎症中的潜在作用及其潜在的机制。用液相色谱-串联质谱仪、Western印迹和荧光探针进行的实验表明，氧化三甲胺可诱导人脐静脉内皮细胞(HUVEC)和载脂蛋白E−/−小鼠的动脉炎症。此外，TMAO在体内外均能促进NLRP3的表达，激活caspase-1p20的表达和caspase-1的活性。值得注意的是，caspase-1抑制剂(YVAD)、NLRP3抑制剂(MCC950)以及NLRP3短干扰RNA可减弱TMAO诱导的NLRP3炎症体的激活，从而抑制HUVEC的炎症。氧化三甲胺还能促进活性氧(ROS)的产生，特别是线粒体ROS的产生，同时抑制HUVEC和ApoE−/−小鼠主动脉中锰超氧化物歧化酶2(SOD2)的激活和sirtuin3(Sirtuin3)的表达。线粒体ROS清除剂Mito-Tempo或SIRT3过表达可改善TMAO诱导的内皮NLRP3炎症体激活。相反，TMAO不能进一步抑制SoD2镁，激活NLRP3炎症体，也不能诱导SIRT3短干扰RNA处理的HUVEC和SIRT3−/−小鼠主动脉的炎症。TMAO通过激活NLRP3炎症小体促进血管炎症，NLRP3炎症小体激活部分是通过抑制SIRT3-SOD2-线粒体ROS信号通路介导的。
Trimethylamine‐N‐oxide (TMAO) has recently been identified as a novel and independent risk factor for promoting atherosclerosis through inducing vascular inflammation. However, the exact mechanism is currently unclear. Studies have established a central role of nucleotide‐binding oligomerization domain–like receptor family pyrin domain–containing 3 (NLRP3) inflammasome in the pathogenesis of vascular inflammation. Here, we examined the potential role of the NLRP3 inflammasome in TMAO‐induced vascular inflammation in vitro and in vivo and the underlying mechanisms. Experiments using liquid chromatography‐tandem mass spectrometry, Western blot, and fluorescent probes showed that TMAO‐induced inflammation in human umbilical vein endothelial cells (HUVECs) and aortas from ApoE−/− mice. Moreover, TMAO promoted NLRP3 and activated caspase‐1 p20 expression and caspase‐1 activity in vitro and in vivo. Notably, a caspase‐1 inhibitor (YVAD), an NLRP3 inhibitor (MCC950), as well as NLRP3 short interfering RNA attenuated TMAO‐induced activation of the NLRP3 inflammasome, subsequently leading to suppression of inflammation in HUVECs. TMAO additionally stimulated reactive oxygen species (ROS) generation, in particular, mitochondrial ROS, while inhibiting manganese superoxide dismutase 2 (SOD2) activation and sirtuin 3 (SIRT3) expression in HUVECs and aortas from ApoE−/− mice. TMAO‐induced endothelial NLRP3 inflammasome activation was ameliorated by the mitochondrial ROS scavenger Mito‐TEMPO, or SIRT3 overexpression in HUVECs. Conversely, TMAO failed to further inhibit magnesium SOD2 and activate the NLRP3 inflammasome or induce inflammation in SIRT3 short interfering RNA–treated HUVECs and aortas from SIRT3−/− mice. TMAO promoted vascular inflammation by activating the NLRP3 inflammasome, and the NLRP3 inflammasome activation in part was mediated through inhibition of the SIRT3‐SOD2–mitochondrial ROS signaling pathway.