Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction.
Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction.
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DOI：
10.1159/000484623
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Koka S
中科院分区：
文献类型：
--
作者：
Boini KM;Hussain T;Li PL;Koka S
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，最近已与啮齿动物和人类的动脉粥样硬化和心血管疾病（CVD）风险增加有关。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NLRP 3炎性小体形成和活化，从而有助于引发动脉粥样硬化的内皮损伤。共聚焦显微镜检测炎症小体形成和活化，比色法检测caspase-1活性，ELISA法检测IL-1β产生，酶标仪检测细胞通透性，Western blot和共聚焦显微镜检测ZO-1表达。在体内实验中，通过渗透泵植入来输注TMAO。与对照细胞相比，TMAO处理显著增加NLRP 3与Asc或NLRP 3与caspase-1的共定位、caspase-1活性、IL-1β产生、细胞通透性。caspase-1抑制剂、WEHD或Nlrp 3 siRNA预处理可抑制TMAO诱导的炎性小体形成、活化和细胞通透性。此外，我们还探讨了TMAO激活NLRP 3炎性小体的机制。TMAO诱导的NLRP 3炎性体的活化与氧化还原调节和溶酶体功能障碍相关。在动物实验中，发现在颈动脉部分结扎的小鼠中直接输注TMAO增加了野生型小鼠内膜中的NLRP 3炎性小体形成和IL-1β产生。TMAO对NLRP 3炎性小体的形成和激活可能是开启内皮炎症反应导致内皮功能障碍的重要启动机制。
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. Inflammasome formation and activation was determined by confocal microscopy, caspase-1 activity was measured by colorimetric assay, IL-1β 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. TMAO treatment significantly increased the colocalization of NLRP3 with Asc or NLRP3 with caspase-1, caspase-1 activity, IL-1β 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-1β production in the intima of wild type mice. 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.
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DOI：
10.1016/j.bbamcr.2014.11.012
发表时间：
2015-02
影响因子：
5.1
作者：
Chen, Yang;Li, Xiang;Boini, Krishna M.;Pitzer, Ashley L.;Gulbins, Erich;Zhang, Yang;Li, Pin-Lan
通讯作者：
Li, Pin-Lan
影响因子：
--
作者：
Boini KM;Xia M;Koka S;Gehr TW;Li PL
通讯作者：
Li PL
影响因子：
3.7
作者：
Rajamäki K;Lappalainen J;Oörni K;Välimäki E;Matikainen S;Kovanen PT;Eklund KK
通讯作者：
Eklund KK
氧化还原依赖性内皮 Nlrp3 炎症小体激活对高血糖诱导的内皮功能障碍的影响
DOI：
10.1007/s00109-016-1481-5
发表时间：
2016-12
期刊：
Journal of molecular medicine (Berlin, Germany)
影响因子：
--
作者：
Chen Y;Wang L;Pitzer AL;Li X;Li PL;Zhang Y
通讯作者：
Zhang Y
影响因子：
4.7
作者：
Li, Xiang;Han, Wei-Qing;Boini, Krishna M.;Xia, Min;Zhang, Yang;Li, Pin-Lan
通讯作者：
Li, Pin-Lan