Protective effect of vitexin against high fat-induced vascular endothelial inflammation through inhibiting trimethylamine N -oxide-mediated RNA m6A modification.

A high-fat diet (HFD) is a major risk factor for cardiovascular disease. However, the specific effects of a HFD on vascular inflammation and the protective role of vitexin, a bioactive compound derived from food, require further research. This study investigated the protective effects of vitexin intervention against HFD-induced vascular inflammation and its underlying mechanism. The results demonstrated that vitexin intervention significantly reduced body weight, serum total cholesterol, and low-density lipoprotein cholesterol levels in HFD-fed mice. Vitexin also improved vascular pathological changes and the inflammatory status in the mice. Furthermore, vitexin intervention reduced serum TMAO levels in HFD-fed mice by altering the gut microbiota composition. The HFD significantly increased N 6-methyladenosine (m6A) levels in aorta tissues, while vitexin intervention reversed this abnormal m6A level. Through metabolite affinity responsive target fluorescence quenching and molecular docking assays, it was found that vitexin could directly bind to fat mass and obesity-associated protein (FTO), potentially promoting m6A demethylation. The dose-response relationship between TMAO and inflammation/m6A was further validated in HUVEC cells and in vivo mouse experiments. Specifically, TMAO increased m6A levels and inflammation, while vitexin inhibited TMAO-mediated m6A modification, exhibiting anti-inflammatory effects. In conclusion, this study demonstrates the protective role of vitexin against HFD-induced vascular inflammation by inhibiting TMAO-mediated RNA m6A modification, laying the foundation for the development of functional foods.