Trimethylamine N-oxide (TMAO) and Atherosclerosis: the Potential Role of Specific Histone Hypomethylation
Open Access
- Author:
- Bach, Elisabeth Rose
- Area of Honors:
- Nutritional Sciences
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Maria Rita Castro, Thesis Supervisor
Alison Diane Gernand, Thesis Honors Advisor - Keywords:
- Trimethylamine N-oxide
TMAO
Atherosclerosis
Hypomethylation
Histone methylation
cardiovascular disease
methyl metabolism
HUVEC
S-Adenosylhomocysteine
SAH
Endothelial dysfunction
Vascular endothelium - Abstract:
- Background: Cardiovascular disease, the global leading cause of death, is a result of atherosclerosis, a pathological condition characterized by inflammation, endothelial cell dysfunction and plaque formation in the vascular system. Increased levels of trimethylamine N-oxide (TMAO), a microbial byproduct of dietary choline, betaine, and carnitine, have been associated with atherosclerosis development; however, the molecular mechanisms which underlie this association are not fully understood. Because previous research has disclosed a link between decreased trimethylation of histone H3 on lysine 27 (H3K27me3), vascular inflammation, endothelial dysfunction, and atherosclerosis, this study aimed to determine whether the same molecular mechanism, i.e. specific histone hypomethylation, could contribute to the vascular toxicity of TMAO. Methods and results: Studies were conducted on human umbilical vein endothelial cells under TMAO treatment as compared to positive and negative controls. First, the effects of TMAO on translational levels of relevant genes (associated with atherosclerosis) were assessed using real time quantitative polymerase chain reactions (RT-qPCR). Nevertheless, the obtained results were unclear, thus requiring further investigation. Afterwards, In-Cell Western blotting was used to quantify the endothelial cell content of H3K27me3, which was found to be significantly decreased by TMAO treatment (after 24 hours, in unsupplemented media). Finally, profiting from an ongoing experiment in which apoE-deficient mice were being fed either atherogenic or control diets, plasma TMAO levels from both groups were quantified. The results showed a concomitant increase in atherosclerotic plaque coverage and serum TMAO concentrations. Conclusions: Overall, suppression of H3K27 trimethylation may contribute to the vascular toxicity associated with increased plasma TMAO concentrations, however, additional investigation is necessary.