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

The high-fat diet (HFD) is a major risk factor for cardiovascular disease. However, the specific effects of HFD on vascular inflammation and the protective role of vitexin, a bioactive small-molecule 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 inflammatory status in the mice. Furthermore, vitexin intervention reduced serum TMAO levels in HFD-fed mice and achieved this effect by altering gut microbiota composition. HFD significantly increased N6-methyladenosine (m6A) levels in aorta tissues, while vitexin intervention reversed this abnormal m6A level. 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 cell 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 and laying the foundation for the development of functional foods.