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

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 (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.

SUBMITTER: Brunt VE

PROVIDER: S-EPMC7295014 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background & aimsNitric oxide bioactivity (NO) from endothelial NO synthase (eNOS) importantly contributes to the maintenance of vascular homeostasis, and reduced eNOS activity has been associated with cardiovascular disease. Emerging evidence suggests interaction(s) between red blood cells (RBCs) and the endothelium in vascular control; however, the specific role of RBC eNOS is less clear. We aimed to investigate the hypothesis that a lack of RBC eNOS induces endothelial dysfunction.Methods & resultsRBCs from global eNOS knockout (KO) and wildtype (WT) mice were co-incubated ex vivo overnight with healthy mouse aortic rings, followed by functional and mechanistic analyses of endothelium-dependent and independent relaxations. RBCs from eNOS KO mice induced endothelial dysfunction and vascular oxidative stress, whereas WT RBC did not. No differences were observed for endothelium-independent relaxations. This eNOS KO RBC-induced endothelial dysfunctional phenotype was prevented by concomitant co-incubation with reactive oxygen species scavenger (TEMPOL), arginase inhibitor (nor-NOHA), NO donor (detaNONOate) and NADPH oxidase 4 (NOX4) inhibitor. Moreover, vessels from endothelial cell-specific arginase 1 KO mice were resistant to eNOS KO-RBC-induced endothelial dysfunction. Finally, in mice aortae co-incubated with RBCs from women with preeclampsia, we observed a significant reduction in endothelial function compared to when using RBCs from healthy pregnant women or from women with uncomplicated gestational hypertension.ConclusionsRBCs from mice lacking eNOS, and patients with preeclampsia, induce endothelial dysfunction in adjacent blood vessels. Thus, RBC-derived NO bioactivity acts to prevent induction of vascular oxidative stress occurring via RBC NOX4-derived ROS in a vascular arginase-dependent manner. Our data highlight the intrinsic protective role of RBC-derived NO bioactivity in preventing the damaging potential of RBCs. This provides novel insight into the functional relationship between RBCs and the vasculature in health and cardiovascular disease, including preeclampsia.

Project description:Vascular endothelial dysfunction develops with aging, as indicated by impaired endothelium-dependent dilation, and is related to increased cardiovascular disease risk. We hypothesized that short-term treatment with fenofibrate, a lipid-lowering agent with potential pleiotropic effects, would improve endothelium-dependent dilation in middle-aged and older normolipidemic adults by reducing oxidative stress. Brachial artery flow-mediated dilation, a measure of endothelium-dependent dilation, was assessed in 22 healthy adults aged 50 to 77 years before and after 7 days of fenofibrate (145 mg/d; n=12) or placebo (n=10). Brachial flow-mediated dilation was unchanged with placebo, but improved after 2 and 7 days of fenofibrate (5.1 ± 0.7 versus 2 days: 6.0 ± 0.7 and 7 days: 6.4 ± 0.6%δ; both P<0.005). The improvements in flow-mediated dilation after 7 days remained significant (P<0.05) after accounting for modest changes in plasma total and low-density lipoprotein cholesterol. Endothelium-independent dilation was not affected by fenofibrate or placebo (P>0.05). Intravenous infusion of the antioxidant vitamin C improved brachial flow-mediated dilation at baseline in both groups and during placebo treatment (P<0.05), but not after 2 and 7 days of fenofibrate (P>0.05). Fenofibrate treatment also reduced plasma-oxidized low-density lipoprotein, a systemic marker of oxidative stress, compared with placebo (P<0.05). In vascular endothelial cells sampled from peripheral veins of the subjects, endothelial nitric oxide synthase protein expression was unchanged with placebo and after 2 days of fenofibrate, but was increased after 7 days of fenofibrate (0.54 ± 0.03 versus 2 days: 0.52 ± 0.04 and 7 days: 0.76 ± 0.11 intensity/human umbilical vein endothelial cell control; P<0.05, 7 days). Short-term treatment with fenofibrate improves vascular endothelial function in healthy normolipidemic middle-aged and older adults by reducing oxidative stress and induces an increase in endothelial nitric oxide synthase.

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

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