Trimethylamine-N-Oxide Induces Vascular Inflammation by Activating the NLRP3 Inflammasome Through the SIRT3-SOD2-mtROS Signaling Pathway.

ABSTRACT: 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.

SUBMITTER: Chen ML 

PROVIDER: S-EPMC5634285 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other