Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway
BackgroundTrimethylamine‐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 oligomeri...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2017-09-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.117.006347 |
| _version_ | 1811328968895234048 |
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| author | Ming‐liang Chen Xiao‐hui Zhu Li Ran He‐dong Lang Long Yi Man‐tian Mi |
| author_facet | Ming‐liang Chen Xiao‐hui Zhu Li Ran He‐dong Lang Long Yi Man‐tian Mi |
| author_sort | Ming‐liang Chen |
| collection | DOAJ |
| description | BackgroundTrimethylamine‐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. Methods and ResultsExperiments 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 SOD2 and activate the NLRP3 inflammasome or induce inflammation in SIRT3 short interfering RNA–treated HUVECs and aortas from SIRT3−/− mice. ConclusionsTMAO 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. |
| first_indexed | 2024-04-13T15:35:22Z |
| format | Article |
| id | doaj.art-491b6c094b144ba0bb0c861393a49b1c |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-13T15:35:22Z |
| publishDate | 2017-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-491b6c094b144ba0bb0c861393a49b1c2022-12-22T02:41:17ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802017-09-016910.1161/JAHA.117.006347Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling PathwayMing‐liang Chen0Xiao‐hui Zhu1Li Ran2He‐dong Lang3Long Yi4Man‐tian Mi5Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, ChinaResearch Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, ChinaResearch Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, ChinaResearch Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, ChinaResearch Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, ChinaResearch Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, ChinaBackgroundTrimethylamine‐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. Methods and ResultsExperiments 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 SOD2 and activate the NLRP3 inflammasome or induce inflammation in SIRT3 short interfering RNA–treated HUVECs and aortas from SIRT3−/− mice. ConclusionsTMAO 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.https://www.ahajournals.org/doi/10.1161/JAHA.117.006347atherosclerosisNOD‐like receptor family pyrin domain containing 3 inflammasomesirtuin 3trimethylamine‐N‐oxidevascular inflammation |
| spellingShingle | Ming‐liang Chen Xiao‐hui Zhu Li Ran He‐dong Lang Long Yi Man‐tian Mi Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease atherosclerosis NOD‐like receptor family pyrin domain containing 3 inflammasome sirtuin 3 trimethylamine‐N‐oxide vascular inflammation |
| title | Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway |
| title_full | Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway |
| title_fullStr | Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway |
| title_full_unstemmed | Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway |
| title_short | Trimethylamine‐N‐Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3‐SOD2‐mtROS Signaling Pathway |
| title_sort | trimethylamine n oxide induces vascular inflammation by activating the nlrp3 inflammasome through the sirt3 sod2 mtros signaling pathway |
| topic | atherosclerosis NOD‐like receptor family pyrin domain containing 3 inflammasome sirtuin 3 trimethylamine‐N‐oxide vascular inflammation |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.117.006347 |
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