Scientists have found that trimethylamine (TMAO), which is formed in the liver of the waste products of the intestinal microbiome, provokes oxidative stress which leads to endothelial dysfunction of blood vessels. As noted in the article, published in the journal Hypertension, with age, the concentration of TMAO in the plasma increases, which leads to inactivation of endothelial nitric oxide synthases activation and oxidative stress. Both of these processes directly contribute to endothelial dysfunction, which starts the process of atherosclerosis.
Endothelial dysfunction is an important precursor to and an early marker of atherosclerosis, which is involved in the pathogenesis of most cardiovascular diseases. In this state of endothelial cells (the epithelium covering vessels from the inside) is worse synthesize important humoral substances, monitoring the condition of the blood and the vessels: clotting factors and regulators of vascular tone, the most important of which is endothelial synthase nitric oxide (eNOS). Nitric oxide relaxes the smooth muscles of blood vessels, causing them to dilate and blood pressure falls. If its synthesis is disrupted, vessels are able to relax and the blood pressure remains elevated, which increases the risk of developing cardiovascular disease.
A group of scientists under the leadership of Douglas Sills (Douglas R. Seals) from the University of Colorado at boulder investigated how the concentration of trimethylaminuria in the blood plasma changes with age, and what effect it has on blood vessels. TMAO is formed in the liver from precursor trimethylamine (TMA). It, in turn, synthesizes the intestinal microflora of choline, L-carnitine (vitamin-like substances B4) and betaine, dietary.
Previous studies showedthat the concentration of TMAO in the blood plasma is higher in old male mice (26-28 months) compared to young (6-8 months). For the control of this study one group of young male mice were fed choline diet and the other with a content of 0.12 per cent of TMAO within 6 months. The control group was fed regular food. The concentration of TMAO in the blood plasma were significantly increased in mice treated with TMAO (31,5 ± 9,5 moles per liter) compared to control (2,9 ± 0,4 moles per liter, p < 0.05), but TMAO did not affect the concentration of precursors of TMAO in plasma (R > 0,45). The addition of TMAO did not affect body weight, appetite and weight of key organs (p < 0,27).
Endothelium-dependent enlargement of the vessel occurs under the action produced by the endothelium nitric oxide. This expansion of the carotid artery in increasing doses of acetylcholine (the neurotransmitter that triggers the synthesis of nitric oxide in the endothelium) were significantly lower in the group with the addition of TMAO (p < 0.01). Scientists have found that this vasodilatation is directly related to reduced bioavailability of nitric oxide.
Scientists have suggested that the decreased bioavailability of nitric oxide may be associated with a decrease of its production by endothelial sintasas of nitric oxide, or increased destruction in the reactions of oxidative stress. They found that the content of phosphorylated eNOS, a well-proven marker of the active form of the enzyme, was lower in the aortas of mice with addition of TMAO compared with the control (p < 0.05). The contents of nitrotyrosine indicator of oxidative modification of tyrosine residues in proteins and a marker of oxidative stress was also different in the two groups of mice. In aortas of mice that were fed with additives TMAO, nitrotyrosine was 2 times greater than in mice from the control group (p < 0.05).
Finally, to confirm the activation of superoxide dismutase, which is opposed to the oxidative stress, the researchers tested the amount of extension of the carotid artery in increasing doses of acetylcholine after administration of the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxide (TEMPOL). TEMPOL restored endothelial dependent expansion of carotid arteries in mice that were fed food with the addition of TMAO to the level observed in the control group (p < 0.05), but it had no effect on dilation of the arteries in mice from the control group. Thus, scientists have shown that TMAO affects the bioavailability of nitric oxide due to its destruction in reactions of oxidative stress and may reduce the work of eNOS. TMAO worsen the function of vascular endothelium, promoting superoxide oxidative stress in the absence of a clear increase in proinflammatory signaling and expression of cytokines.