| Autor: |
Brunt VE; From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., R.A.G.-R., A.G.C., N.S.V., B.P.Z., Z.J.S., J.J.R., M.C.Z., D.R.S.)., Gioscia-Ryan RA; From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., R.A.G.-R., A.G.C., N.S.V., B.P.Z., Z.J.S., J.J.R., M.C.Z., D.R.S.)., Casso AG; From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., R.A.G.-R., A.G.C., N.S.V., B.P.Z., Z.J.S., J.J.R., M.C.Z., D.R.S.)., VanDongen NS; From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., R.A.G.-R., A.G.C., N.S.V., B.P.Z., Z.J.S., J.J.R., M.C.Z., D.R.S.)., Ziemba BP; From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., R.A.G.-R., A.G.C., N.S.V., B.P.Z., Z.J.S., J.J.R., M.C.Z., D.R.S.)., Sapinsley ZJ; From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., R.A.G.-R., A.G.C., N.S.V., B.P.Z., Z.J.S., J.J.R., M.C.Z., D.R.S.)., Richey JJ; From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., R.A.G.-R., A.G.C., N.S.V., B.P.Z., Z.J.S., J.J.R., M.C.Z., D.R.S.)., Zigler MC; From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., R.A.G.-R., A.G.C., N.S.V., B.P.Z., Z.J.S., J.J.R., M.C.Z., D.R.S.)., Neilson AP; Department of Food Science and Technology (A.P.N.), Virginia Tech, Blacksburg., Davy KP; Department of Human Nutrition, Foods, and Exercise (K.P.D.), Virginia Tech, Blacksburg., Seals DR; From the Department of Integrative Physiology, University of Colorado Boulder (V.E.B., R.A.G.-R., A.G.C., N.S.V., B.P.Z., Z.J.S., J.J.R., M.C.Z., D.R.S.). |
| Abstrakt: |
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 <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 (N 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. |
