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J Am Heart Assoc. 2016 Feb 22;5(2). pii: e002767. doi: 10.1161/JAHA.115.002767.

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

Author information

1
Department of Medicine, Cardiology Division at the University of California, Los Angeles, CA.
2
Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH.
3
Department of Medicine, Cardiology Division at the University of California, Los Angeles, CA dshih@mednet.ucla.edu.

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.

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.

KEYWORDS:

atherosclerosis; cardiovascular disease; endothelial cell; inflammation; leukocyte adhesion; nuclear factor‐κB signaling; trimethylamine N‐oxide; vascular smooth muscle cell

PMID:
26903003
PMCID:
PMC4802459
DOI:
10.1161/JAHA.115.002767
[Indexed for MEDLINE]
Free PMC Article

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