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首页> 外文期刊>Cellular Physiology and Biochemistry >Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction
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Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction

机译：三甲胺-N-氧化物可促进NLRP3炎性小体活化和内皮功能障碍。

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>Background/Aim: Plasma trimethylamine-N-oxide (TMAO), a product of intestinal microbial metabolism of dietary phosphatidylcholine has been recently associated with atherosclerosis and increased risk of cardiovascular diseases (CVD) in rodents and humans. However, the molecular mechanisms of how TMAO induces atherosclerosis and CVD progression are still unclear. The present study tested whether TMAO induces NLRP3 inflammasome formation and activation and thereby contributes to endothelial injury initiating atherogenesis. Methods: Inflammasome formation and activation was determined by confocal microscopy, caspase-1 activity was measured by colorimetric assay, IL-1?2 production was measured using ELISA, cell permeability was determined by microplate reader and ZO-1 expression was determined by western blot analysis and confocal microscopy. In in vivo experiments, TMAO was infused by osmotic pump implantation. Results: TMAO treatment significantly increased the colocalization of NLRP3 with Asc or NLRP3 with caspase-1, caspase-1 activity, IL-1?2 production, cell permeability in carotid artery endothelial cells (CAECs) compared to control cells. Pretreatment with caspase-1 inhibitor, WEHD or Nlrp3 siRNA abolished the TMAO-induced inflammasome formation, activation and cell permeability in these cells. In addition, we explored the mechanisms by which TMAO activates NLRP3 inflammasomes. TMAO-induced the activation of NLRP3 inflammasomes was associated with both redox regulation and lysosomal dysfunction. In animal experiments, direct infusion of TMAO in mice with partially ligated carotid artery were found to have increased NLRP3 inflammasome formation and IL-1?2 production in the intima of wild type mice. Conclusion: The formation and activation of NLRP3 inflammasomes by TMAO may be an important initiating mechanism to turn on the endothelial inflammatory response leading to endothelial dysfunction.
机译：> 背景/目的： 血浆三甲胺-N-氧化物（TMAO）是膳食磷脂酰胆碱的肠道微生物代谢产物，最近与动脉粥样硬化相关，并增加了患上动脉粥样硬化的风险。啮齿动物和人类的心血管疾病（CVD）。然而，TMAO如何诱导动脉粥样硬化和CVD进展的分子机制仍不清楚。本研究测试了TMAO是否诱导NLRP3炎性小体的形成和激活，从而有助于内皮损伤引发动脉粥样硬化。 方法： 通过共聚焦显微镜确定炎症小体的形成和活化，通过比色法测量caspase-1的活性，使用ELISA法测量IL-1？2的产生，细胞通透性用酶标仪测定DNA，用Western印迹分析和共聚焦显微镜测定ZO-1的表达。在体内实验中，通过渗透泵植入注入了TMAO。 结果： TMAO治疗显着增加了NLRP3与Asc或NLRP3与caspase-1，caspase-1活性，IL-1？2产生，颈动脉动脉通透性的共定位内皮细胞（CAEC）与对照细胞相比。用caspase-1抑制剂，WEHD或Nlrp3 siRNA进行的预处理消除了TMAO诱导的这些细胞中炎性体的形成，活化和细胞通透性。此外，我们探索了TMAO激活NLRP3炎性小体的机制。 TMAO诱导的NLRP3炎性体的激活与氧化还原调节和溶酶体功能障碍有关。在动物实验中，发现在部分结扎颈动脉的小鼠中直接输注TMAO具有增加野生型小鼠内膜中NLRP3炎性体形成和IL-1β2产生的作用。 结论： TMAO对NLRP3炎性小体的形成和激活可能是开启引起内皮功能障碍的炎症反应的重要启动机制。

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