Trimethylamine-N-Oxide Promotes Age-Related Vascular Oxidative Stress and Endothelial Dysfunction in Mice and Healthy Humans
| Autor: | Vienna E. Brunt, Andrew P. Neilson, Kevin P. Davy, Douglas R. Seals, Zachary J Sapinsley, Rachel A. Gioscia-Ryan, Brian P. Ziemba, Nicholas S. VanDongen, Abigail G. Casso, Melanie C. Zigler, James J Richey |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty 030204 cardiovascular system & hematology medicine.disease_cause Superoxide dismutase 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine.artery Internal Medicine medicine Endothelial dysfunction Brachial artery biology Superoxide business.industry Nitrotyrosine Ascorbic acid medicine.disease Nitric oxide synthase 030104 developmental biology Endocrinology chemistry biology.protein business Oxidative stress |
| Zdroj: | Hypertension. 76:101-112 |
| ISSN: | 1524-4563 0194-911X |
| Popis: | 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 ( r 2 =0.29, P P G -nitro-L-arginine methyl ester). Acute incubation of carotid arteries with trimethylamine-N-oxide recapitulated these events. Next, treatment with 3,3-dimethyl-1-butanol for 8 to 10 weeks to suppress trimethylamine-N-oxide selectively improved endothelium-dependent dilation in old mice to young levels (peak: 90±2%) by normalizing vascular superoxide production, restoring nitric oxide-mediated dilation, and ameliorating superoxide-related suppression of endothelium-dependent dilation. Lastly, among healthy middle-aged/older adults, higher plasma trimethylamine-N-oxide was associated with greater nitrotyrosine abundance in biopsied endothelial cells, and infusion of the antioxidant ascorbic acid restored flow-mediated dilation to young levels, indicating tonic oxidative stress-related suppression of endothelial function with higher circulating trimethylamine-N-oxide. Using multiple experimental approaches in mice and humans, we demonstrate a clear role of trimethylamine-N-oxide in promoting age-related endothelial dysfunction via oxidative stress, which may have implications for prevention of cardiovascular diseases. |
| Databáze: | OpenAIRE |
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