Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB

Abstract

BackgroundThe choline‐derived metabolite trimethylamine N‐oxide (TMAO) has been demonstrated to contribute to atherosclerosis and is associated with coronary artery disease risk.Methods and ResultsWe explored the impact of TMAO on endothelial and smooth muscle cell function in vivo, focusing on disease‐relevant outcomes for atherogenesis. Initially, we observed that aortas of LDLR −/− mice fed a choline diet showed elevated inflammatory gene expression compared with controls. Acute TMAO injection at physiological levels was sufficient to induce the same inflammatory markers and activate the well‐known mitogen‐activated protein kinase, extracellular signal–related kinase, and nuclear factor‐κB signaling cascade. These observations were recapitulated in primary human aortic endothelial cells and vascular smooth muscle cells. We also found that TMAO promotes recruitment of activated leukocytes to endothelial cells. Through pharmacological inhibition, we further showed that activation of nuclear factor‐κB signaling was necessary for TMAO to induce inflammatory gene expression in both of these relevant cell types as well as endothelial cell adhesion of leukocytes.ConclusionsOur results suggest a likely contributory mechanism for TMAO‐dependent enhancement in atherosclerosis and cardiovascular risks.

Microbial modulation of cardiovascular disease

“…This is, in large part, due to the lack of understanding of the molecular sensor for TMAO (that is, the TMAO receptor). Although there is evidence that TMAO can function as an important osmolyte in biological systems 78,79 , more recent evidence suggest that TMAO can rapidly signal to cells within minutes 8,80 . In isolated platelets, brief exposures to physiological levels of TMAO can potentiate thrombin-induced calcium release 8 .…”

“…In isolated platelets, brief exposures to physiological levels of TMAO can potentiate thrombin-induced calcium release 8 . Likewise, treatment with TMAO in endothelial cells or smooth muscle cells, or direct injection in vivo, was shown to rapidly induce the activation of mitogen-activated protein kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), or the upregulation of downstream adhesion proteins on aortic endothelial cells 80 . The kinetics of these TMAO-induced signaling responses strongly suggest that host cells may possess a dedicated receptor or sensor system to transduce the TMAO signal to an appropriate cellular response (FIG 2).…”

The role of trimethylamine N-oxide as a mediator of cardiovascular complications in chronic kidney disease

“…18 Several pro-inflammatory mediators including Cyclo-oxygenase-2 (COX-2), E-Selectin and Intracellular Adhesion Molecule-1 (ICAM-1) were upregulated in the aortic tissue of low-density lipoprotein receptor knock-out (LDLr-/-) mice receiving dietary choline or intraperitoneal TMAO. 35 In vitro, TMAO enhanced leucocyte adhesion to endothelial cells in an NF-κB-dependent manner. 35 Furthermore, enhanced platelet activation and adhesion has been observed following intraperitoneal TMAO injections in an in vivo carotid artery injury model.…”

“…35 In vitro, TMAO enhanced leucocyte adhesion to endothelial cells in an NF-κB-dependent manner. 35 Furthermore, enhanced platelet activation and adhesion has been observed following intraperitoneal TMAO injections in an in vivo carotid artery injury model. 36 …”

Trimethylamine Oxide (TMAO): A New Toxic Kid on the Block

“…Studies on both in vivo and in vitro cultured human aortic endothelial cells and vascular smooth muscle cells showed that elevated levels of TMAO induce expression of proinflammatory cytokines and adhesion molecules mediated by the NF-κB signaling pathway [18]. TMAO enhances monocyte activation as well as adhesion by activating endothelial cells to express VCAM-1 [19,20].…”