Abstract
Diet is a well-known risk factor of cardiovascular diseases (CVDs). Some microRNAs (miRNAs) have been described to regulate molecular pathways related to CVDs. Diet can modulate miRNAs and their target genes. Choline, betaine, and l-carnitine, nutrients found in animal products, are metabolized into trimethylamine n-oxide (TMAO), which has been associated with CVD risk. The aim of this study was to investigate TMAO regulation of CVD-related miRNAs and their target genes in cellular models of liver and macrophages. We treated HEPG-2, THP-1, mouse liver organoids, and primary human macrophages with 6 µM TMAO at different timepoints (4, 8, and 24 h for HEPG-2 and mouse liver organoids, 12 and 24 h for THP-1, and 12 h for primary human macrophages) and analyzed the expression of a selected panel of CVD-related miRNAs and their target genes and proteins by real-time PCR and Western blot, respectively. HEPG-2 cells were transfected with anti-miR-30c and syn-miR-30c. TMAO increased the expression of miR-21-5p and miR-30c-5p. PER2, a target gene of both, decreased its expression with TMAO in HEPG-2 and mice liver organoids but increased its mRNA expression with syn-miR-30c. We concluded that TMAO modulates the expression of miRNAs related to CVDs, and that such modulation affects their target genes.
Highlights
Cardiovascular diseases (CVDs) are the first cause of death amongst developed countries
We demonstrate that trimethylamine n-oxide (TMAO) downregulates PER2, a target gene of both miRNAs, which is involved in circadian rhythms regulation and its disruption has been linked to cardiovascular diseases (CVDs) [41]
This study shows how TMAO, at a physiological dose (6 μM), modulates the expression of miRNAs related to lipid metabolism, atherosclerosis, and CVDs
Summary
Cardiovascular diseases (CVDs) are the first cause of death amongst developed countries. In the US, according to the Centers for Control Disease and Prevention, one in four deaths is caused by CVD, and about 647,000 people die every year (https://www.cdc.gov/nchs/fastats/heart-disease.htm (accessed on 18 August 2021)). In. Europe, 42% of total deaths are caused by a cardiovascular event, constituting the leading cause of death, as well as a decline in quality of life and disability [2]. 42% of total deaths are caused by a cardiovascular event, constituting the leading cause of death, as well as a decline in quality of life and disability [2] This accounts for an annual cost of approximately 200 billion EUR, which represents 54% of total healthcare investment and leads to a 24% loss in productivity [2,3]. Atherosclerosis, i.e., the plaque containing fatty acids, oxidized cholesterol, and calcium that builds within the arterial walls, is the primary cause of CVDs [4], and oxidative stress and inflammation, promoted by cholesterol-loaded macrophages infiltrated in the artery wall, are crucial to the development of atherosclerosis
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