Nitric oxide synthase uncoupling: A therapeutic target in cardiovascular diseases

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.

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INHIBITION OF NITRIC OXIDE SYNTHASE AS A POTENTIAL THERAPEUTIC TARGET

The Annual Review of Pharmacology and Toxicology ◽

10.1146/annurev.pharmtox.39.1.191 ◽

1999 ◽

Vol 39 (1) ◽

pp. 191-220 ◽

Cited By ~ 431

Author(s):

Adrian J. Hobbs ◽

Annie Higgs ◽

Salvador Moncada

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Therapeutic Target ◽

Potential Therapeutic Target ◽

Oxide Synthase

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339 Hypoxia-Inducible Factor 1 Transactivates Neuronal Nitric Oxide Synthase and Is a Potential Therapeutic Target in Gastroparesis

Gastroenterology ◽

10.1016/s0016-5085(16)30385-7 ◽

2016 ◽

Vol 150 (4) ◽

pp. S80

Author(s):

Yujiro Hayashi ◽

Sergiy M. Kvasha ◽

Jeong Heon Lee ◽

Sabriya A. Syed ◽

Huihuang Yan ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Therapeutic Target ◽

Hypoxia Inducible Factor ◽

Neuronal Nitric Oxide Synthase ◽

Potential Therapeutic Target ◽

Hypoxia Inducible Factor 1 ◽

Oxide Synthase

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Nitric Oxide and Related Aspects Underlying Angina

The Open Cardiovascular Medicine Journal ◽

10.2174/1874192401711010033 ◽

2017 ◽

Vol 11 (1) ◽

pp. 33-46 ◽

Cited By ~ 2

Author(s):

Carolina Baraldi Araujo Restini ◽

Leticia Gonçalves

Keyword(s):

Nitric Oxide ◽

Metabolic Syndrome ◽

Cardiovascular Diseases ◽

Nitric Oxide Synthase ◽

Present Review ◽

Number Of Patients ◽

Oxide Synthase

Increased number of patients affected by metabolic syndrome (MS) has prompted the necessity of better understanding what is involved in such syndrome. Nevertheless, the establishment of promising therapies depends on the knowledge about the interaction of molecules within MS. In such context, Nitric Oxide (NO) emerges from a bulk of works relating its roles on aspects of MS, including cardiovascular diseases, their symptoms and comorbidities, which are thought to be triggered by similar sources. NO, nitric oxide synthase and enzymatic chains are keys for those disease and symptoms processes. NO has been separately described as part of hypertensive, ischemic and pain signaling. Although there are similar pathways likely shared for generating cardiovascular symptoms such angina, they are barely associated to NO in literature. The present review aims to clarify the patterns of NO alteration in metabolic syndrome directly concerned to cardiovascular symptoms, especially angina.

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