Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome.
Recent research demonstrates that the choline-derived metabolite trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis and cardiovascular risks. The NLRP3 inflammasome responds to exogenous and endogenous danger signals involved in the development of atherosclerosis. Moreover, thioredoxin-interactive protein (TXNIP) activation is a key event linked to NLRP3 inflammasome via reactive oxygen species (ROS). Whether TMAO prime NLRP3 inflammasome via ROS-TXNIP pathway remains unclear. This study observed the expression of TXNIP-NLRP3 inflammasome stimulated by TMAO in human umbilical vein endothelial cells (HUVECs), aiming to elucidate the mechanism by which the TMAO may contribute to inflammation and endothelial dysfunction. Our data showed that TMAO significantly triggered oxidative stress and activated TXNIP-NLRP3 inflammasome whereat inflammatory cytokines interleukin (IL)-1β and IL-18 were released in a dose- and time-dependent manner, but endothelial nitric oxide synthase (eNOS) and production of nitric oxide (NO) were inhibited. Moreover, TMAO-mediated effects were observably reversed by ROS inhibitor N-acetylcysteine (NAC) treatment or siRNA-mediated knockdown TXPIN and NLRP3. Taken together, our results firstly reveal that TMAO induces inflammation and endothelial dysfunction via activating ROS-TXNIP-NLRP3 inflammasome, suggest a likely mechanism for TMAO-dependent enhancement in atherosclerosis and cardiovascular risks.
Department of Vascular and Thyroid Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, PR China; State Key Laboratory of Quality Research in Chinese Medicine (Macau University of Science and Technology), Avenida Wai Long, Taipa, Macau, PR China.
Xiaolei
X
Sun
Department of Vascular Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, PR China.
Xuefei
X
Jiao
Department of Vascular and Thyroid Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, PR China.
Yarong
Y
Ma
Department of Vascular and Thyroid Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, PR China.
Yong
Y
Liu
Department of Vascular and Thyroid Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, PR China.
Lei
L
Zhang
Department of Vascular and Thyroid Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, PR China. Electronic address: yzhe1573@163.com.
Yanzheng
Y
He
Department of Vascular Surgery, Qingdao Municipal Hospital, Qingdao, Shandong, 266000, PR China. Electronic address: yunhuichen520@163.com.
Yunhui
Y
Chen
D002352:Carrier Proteins / Q000276:immunology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology*; D008744:Methylamines / Q000009:adverse effects*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology
D002352:Carrier Proteins; D058847:Inflammasomes; D008744:Methylamines; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017382:Reactive Oxygen Species; C486715:TXNIP protein, human; C005855:trimethyloxamine
Atherosclerosis; Endothelial dysfunction; NLRP3 inflammasome; Oxidative stress; Trimethylamine N-oxide