Trimethylamine-N-Oxide Promotes Age-Related Vascular Oxidative Stress and Endothelial Dysfunction in Mice and Healthy Humans.

Hypertension
Vienna E BruntDouglas R Seals

Abstract

Age-related vascular endothelial dysfunction is a major antecedent to cardiovascular diseases. We investigated whether increased circulating levels of the gut microbiome-generated metabolite trimethylamine-N-oxide induces endothelial dysfunction with aging. In healthy humans, plasma trimethylamine-N-oxide was higher in middle-aged/older (64±7 years) versus young (22±2 years) adults (6.5±0.7 versus 1.6±0.2 µmol/L) and inversely related to brachial artery flow-mediated dilation (r2=0.29, P<0.00001). In young mice, 6 months of dietary supplementation with trimethylamine-N-oxide induced an aging-like impairment in carotid artery endothelium-dependent dilation to acetylcholine versus control feeding (peak dilation: 79±3% versus 95±3%, P<0.01). This impairment was accompanied by increased vascular nitrotyrosine, a marker of oxidative stress, and reversed by the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl. Trimethylamine-N-oxide supplementation also reduced activation of endothelial nitric oxide synthase and impaired nitric oxide-mediated dilation, as assessed with the nitric oxide synthase inhibitor L-NAME (NG-nitro-L-arginine methyl ester). Acute incubation of carotid arteries with trimethylamine-N-oxi...Continue Reading

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Citations

Jun 26, 2020·Clinical Science·Matthew J RossmanDouglas R Seals
Jun 11, 2020·Hypertension·Joshua A Beckman, Cyndya A Shibao
Dec 8, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Xin ZhaoQilong Wang
Mar 7, 2021·Nutrients·Matthew D WatsonGregory J Grosicki
Jun 12, 2021·American Journal of Physiology. Heart and Circulatory Physiology·Zachary S ClaytonDouglas R Seals
Aug 7, 2021·Clinical Nutrition : Official Journal of the European Society of Parenteral and Enteral Nutrition·Karine Scanci da Silva PontesMárcia Regina Simas Torres Klein
Aug 6, 2021·Cardiovascular Research·Marco WitkowskiStanley L Hazen
Nov 24, 2021·Journal of Cellular Physiology·Nida BuawangpongSiriporn C Chattipakorn
Nov 30, 2021·Journal of Cardiovascular Pharmacology·Francesca SchinzariCarmine Cardillo

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