TMAO Upregulates Members of the miR-17/92 Cluster and Impacts Targets Associated with Atherosclerosis.
Laura Díez-RicotePaloma Ruiz-ValderreyVíctor MicóRuth Blanco-RojoJoao Tomé-CarneiroAlberto DávalosJosé M OrdovásLidia Daimiel RuizPublished in: International journal of molecular sciences (2022)
Atherosclerosis is a hallmark of cardiovascular disease, and lifestyle strongly impacts its onset and progression. Nutrients have been shown to regulate the miR-17/92 cluster, with a role in endothelial function and atherosclerosis. Choline, betaine, and L-carnitine, found in animal foods, are metabolized into trimethylamine (TMA) by the gut microbiota. TMA is then oxidized to TMAO, which has been associated with atherosclerosis. Our aim was to investigate whether TMAO modulates the expression of the miR-17/92 cluster, along with the impact of this modulation on the expression of target genes related to atherosclerosis and inflammation. We treated HepG-2 cells, THP-1 cells, murine liver organoids, and human peripheral mononuclear cells with 6 µM of TMAO at different timepoints. TMAO increased the expression of all analyzed members of the cluster, except for miR-20a-5p in murine liver organoids and primary human macrophages. Genes and protein levels of SERPINE1 and IL-12A increased. Both have been associated with atherosclerosis and cardiovascular disease (CDVD) and are indirectly modulated by the miR-17-92 cluster. We concluded that TMAO modulates the expression of the miR-17/92 cluster and that such modulation could promote inflammation through IL-12A and blood clotting through SERPINE1 expression, which could ultimately promote atherosclerosis and CVD.
Keyphrases
- cardiovascular disease
- poor prognosis
- long non coding rna
- cell proliferation
- long noncoding rna
- endothelial cells
- binding protein
- oxidative stress
- metabolic syndrome
- cardiovascular risk factors
- cell cycle arrest
- genome wide
- physical activity
- coronary artery disease
- small molecule
- peripheral blood
- cell death
- signaling pathway
- heavy metals
- protein protein
- bioinformatics analysis
- genome wide identification