2.7 THE GUT-DERIVED METABOLITE TRIMETHYLAMINE N-OXIDE INDUCES LARGE ELASTIC ARTERY STIFFENING AND ENDOTHELIAL DYSFUNCTION IN YOUNG MICE

DOI

10.1016/j.artres.2017.10.029How to use a DOI?

Abstract

The gut microbiome, an emerging mediator of host physiological function, is adversely altered by aging and many diseases, termed “gut dysbiosis.” One consequence of gut dysbiosis is elevated circulating levels of the gut-derived metabolite trimethylamine N-oxide (TMAO), which has been directly linked to cardiovascular (CV) risk, including the development of atherosclerosis. However, it is unknown whether TMAO mediates arterial dysfunction that precedes the onset of clinical disease, and if so, the underlying mechanisms.

Purpose: To determine whether TMAO independently induces large elastic artery stiffening and endothelial dysfunction via increased superoxide-related oxidative stress.

Method: Twenty young (6 mo) male C57BL/6 mice were fed a chemically-defined choline (0.08–0.09%) diet supplemented without (Control; N = 9) or with (N = 11) 0.12% TMAO for 6 months. Arterial stiffness was assessed as aortic pulse wave velocity (aPWV). Endothelial function was evaluated ex vivo as carotid artery endothelium-dependent dilation (EDD) to increasing doses of acetylcholine (10⁻⁹ to 10⁻⁴M) in the absence or presence of the superoxide dismutase mimetic TEMPOL.

Results: TMAO increased aPWV (Control: 392 ± 20 vs. TMAO: 483 ± 32 cm/sec, p = 0.04) and impaired EDD (peak dilation, Control: 93.7 ± 3.2 vs. TMAO: 79.9 ± 3.4%, p = 0.01).

Suppression of oxidative stress with TEMPOL restored EDD in TMAO-treated animals (peak dilation: 92.1 ± 4.7%, p = 0.46 vs. Control).

Conclusions: TMAO independently induces large elastic artery stiffening and endothelial dysfunction in mice. Dysfunction appears to occur through increases in oxidative stress. These data may explain, at least in part, why TMAO increases CV risk and provide a potential target for prevention/treatment of arterial dysfunction.

Supported by R01 HL134887 & T32 HL007822.

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TY  - JOUR
AU  - Vienna Brunt
AU  - Rachel Gioscia-Ryan
AU  - Zachary Sapinsley
AU  - Melanie Zigler
AU  - James Richey
AU  - Douglas Seals
PY  - 2017
DA  - 2017/12/06
TI  - 2.7 THE GUT-DERIVED METABOLITE TRIMETHYLAMINE N-OXIDE INDUCES LARGE ELASTIC ARTERY STIFFENING AND ENDOTHELIAL DYSFUNCTION IN YOUNG MICE
JO  - Artery Research
SP  - 52
EP  - 52
VL  - 20
IS  - C
SN  - 1876-4401
UR  - https://doi.org/10.1016/j.artres.2017.10.029
DO  - 10.1016/j.artres.2017.10.029
ID  - Brunt2017
ER  -