title: Trimethylamine N-Oxide Promotes Vascular Inflammation Through Signaling of Mitogen-Activated Protein Kinase and Nuclear Factor-κB.
abstract: BACKGROUND
  The choline-derived metabolite trimethylamine N-oxide (TMAO) has been demonstrated to contribute to atherosclerosis and is associated with coronary artery disease risk.
  
  
  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.
authors.affiliation: Department of Medicine, Cardiology Division at the University of California, Los Angeles, CA.
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Seldin
authors.affiliation: Department of Medicine, Cardiology Division at the University of California, Los Angeles, CA.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Department of Medicine, Cardiology Division at the University of California, Los Angeles, CA.
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Qi
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH.
authors.forename: WeiFei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.affiliation: Department of Medicine, Cardiology Division at the University of California, Los Angeles, CA.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: Department of Medicine, Cardiology Division at the University of California, Los Angeles, CA dshih@mednet.ucla.edu.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Shih
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001025:Aortitis / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D050197:Atherosclerosis / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D002794:Choline; D018920:Coculture Techniques; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology; D008744:Methylamines / Q000633:toxicity*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D010641:Phenotype; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D008744:Methylamines; D016328:NF-kappa B; D011973:Receptors, LDL; D020928:Mitogen-Activated Protein Kinases; C005855:trimethyloxamine; D002794:Choline
keywords: atherosclerosis; cardiovascular disease; endothelial cell; inflammation; leukocyte adhesion; nuclear factor‐κB signaling; trimethylamine N‐oxide; vascular smooth muscle cell