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

• Published in: Journal of the American Heart Association Vol. 5; no. 2
• Main Authors: Seldin, Marcus M., Meng, Yonghong, Qi, Hongxiu, Zhu, WeiFei, Wang, Zeneng, Hazen, Stanley L., Lusis, Aldons J., Shih, Diana M.
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.02.2016; Wiley
• Subjects: Animals; Aorta - drug effects; Aorta - enzymology; Aorta - pathology; Aortitis - chemically induced; Aortitis - enzymology; Aortitis - genetics; Aortitis - pathology; atherosclerosis; Atherosclerosis - chemically induced; Atherosclerosis - enzymology; Atherosclerosis - genetics; Atherosclerosis - pathology; cardiovascular disease; Cell Adhesion - drug effects; Cells, Cultured; Choline; Coculture Techniques; Disease Models, Animal; endothelial cell; Endothelial Cells - drug effects; Endothelial Cells - enzymology; Endothelial Cells - pathology; Enzyme Activation; Female; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; inflammation; leukocyte adhesion; Leukocytes - drug effects; Leukocytes - enzymology; Methylamines - toxicity; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinases - metabolism; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - enzymology; Myocytes, Smooth Muscle - pathology; NF-kappa B - metabolism; nuclear factor‐κB signaling; Original Research; Phenotype; Receptors, LDL - deficiency; Receptors, LDL - genetics; Signal Transduction - drug effects; trimethylamine N‐oxide; vascular smooth muscle cell; atherosclerosis; cardiovascular disease; inflammation; endothelial cell; nuclear factor‐κB signaling; vascular smooth muscle cell; leukocyte adhesion; trimethylamine N‐oxide
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.115.002767

Background The choline‐derived metabolite trimethylamine N‐oxide (TMAO) has been demonstrated to contribute to atherosclerosis and is associated with coronary artery disease risk. Methods and Results We 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. Conclusions Our results suggest a likely contributory mechanism for TMAO‐dependent enhancement in atherosclerosis and cardiovascular risks.