Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome

Sun, Xiaolei; Jiao, Xuefei; Ma, Yarong; Liu, Yong; Zhang, Lei; He, Yanzheng; Chen, Yun-Hui

doi:10.1016/j.bbrc.2016.11.017

Cited by 356 publications

(279 citation statements)

References 27 publications

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“…While the studies show the ability of TMAO to promote atherosclerosis [10,11,17,18,30,31], there are numerous contrasting results [19,[32][33][34][35][36]. Treatment of male Fischer 344 rats by L-carnitine in drinking water for 1 year induced tenfold higher TMAO plasma concentration when compared to the control (2.5 vs. 25.0 μM) [36].…”

Section: Discussion/conclusionmentioning

confidence: 99%

“…Ma et al [18], using human umbilical vein endothelial cells, demonstrated that TMAO up-regulates VCAM-1 expression and promotes monocyte adhesion. In the same human umbilical vein endothelial cells model, TMAO promotes early pathological process of atherosclerosis by accelerating inflammation and triggering oxidative stress [17,30,31].…”

Section: Discussion/conclusionmentioning

confidence: 99%

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L-Carnitine Supplementation Increases Trimethylamine-N-Oxide but not Markers of Atherosclerosis in Healthy Aged Women

et al. 2018

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Background: L-carnitine can be metabolized to trimethylamine N-oxide (TMAO), a molecule that promotes atherogenesis through its interaction with macrophages and lipid metabolism. Objective: The aim of the present study was to assess whether L-carnitine supplementation may promote changes in selected serum biomarkers of atherosclerosis. Methods: Before the start, in the mid-point and after completing the 24-weeks supplementation protocol, fasting blood samples were taken from the antecubital vein. Plasma free L-carnitine and TMAO were determined by the UPLC/MS/MS method. Serum proteins were determined by the enzyme immunoassay method using commercially available kits. Total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and triglycerides have been determined using standard automatic analyzer. Results: L-carnitine supplementation elevated fasting plasma carnitine in the mid-point of our study and it remained increased until the end of supplementation period. Moreover, it induced tenfold increase in plasma TMAO concentration but did not affect serum C-reactive protein, interleukin-6, tumour necrosis factor-α, L-selectin, P-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1 or lipid profile markers. Conclusion: We demonstrated that although oral L-carnitine supplementation significantly increased plasma TMAO concentration, no lipid profile changes or other markers of adverse cardiovascular events were detected in healthy aged women over the period of 24 weeks.

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Section: Discussion/conclusionmentioning

confidence: 99%

Section: Discussion/conclusionmentioning

confidence: 99%

L-Carnitine Supplementation Increases Trimethylamine-N-Oxide but not Markers of Atherosclerosis in Healthy Aged Women

et al. 2018

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“…More interestingly, some non-atherogenic endanger factors also activate NLRP3 inflammasomes including adenosine triphosphate (ATP), uric acid, visfatin and DAMPs [26, 28, 30, 34, 50–53], which may enhance the susceptibility to atherosclerosis or other vascular diseases, cell pyroptosis and alterations of cell membrane permeability, turning on the inflammatory response and directly inducing cell dysfunction or injury. Moreover, recent study shows that TMAO activates the expression of inflammasomes in human umbilical vein endothelial cells [54]. However, it remains unknown whether TMAO induces NLRP3 inflammasomes activation in both in vitro and in vivo and how activated NLRP3 inflammasomes lead to endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction

Boini

Hussain

et al. 2017

Cell Physiol Biochem

201

158

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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-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. Results: 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. 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.

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“…[77][78][79][80][81] In a large number of cell culture studies, NAC has been reported to inhibit inflammasome activation and IL-1β production. [82][83][84][85][86][87][88] However, these studies do not clarify whether increased glutathione mediates this effect or whether the direct scavenging activity of NAC does; in the latter case, these effects might be of limited clinical relevance. Further research to clarify this point could be worthwhile.…”

Section: Oxidative Stress and Inflammasome Activationmentioning

confidence: 97%

Supplemental N-acetylcysteine and other measures that boost intracellular glutathione can downregulate interleukin-1β signalling: a potential strategy for preventing cardiovascular events?

2017

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Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome

Cited by 356 publications

References 27 publications

L-Carnitine Supplementation Increases Trimethylamine-N-Oxide but not Markers of Atherosclerosis in Healthy Aged Women

L-Carnitine Supplementation Increases Trimethylamine-N-Oxide but not Markers of Atherosclerosis in Healthy Aged Women

Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction

Supplemental N-acetylcysteine and other measures that boost intracellular glutathione can downregulate interleukin-1β signalling: a potential strategy for preventing cardiovascular events?

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