Trimethylamine-N-oxide promotes vascular aging via inhibiting GATA4 degradation in chronic kidney disease rats.

A high percentage of chronic kidney disease (CKD) patients suffer from vascular aging. It has been demonstrated that trimethylamine N-oxide (TMAO) is an important indicator of cardiovascular events in patients with CKD. However, there is no clear understanding of how TMAO contributes to vascular aging in CKD. According to our findings, TMAO induced vascular aging in aged rats under normal physiological conditions, and additionally exacerbated vascular aging in young rats with kidney failure. When young rats undergo a 5/6 nephrectomy to build a CKD model, TMAO could cause vascular aging, indicated by upregulated senescence markers including senescence-associated β-galactosidase, p16, p21, p53, vascular dysfunction, and remodeling. By contrast, a reduction in the levels of TMAO by antibiotic treatment attenuated the aging of the arteries in rats with CKD. Also, TMAO was shown to positively regulate senescence in both human umbilical vein endothelial cells (HUVECs) and human vascular smooth muscle cells. A further observation was that TMAO inhibited GATA4 degradation, which resulted in activating the nuclear factor κB signal thus stimulating senescence-associated secretory phenotype during aging. By contrast, silencing of GATA4 attenuated TMAO-induced senescence in HUVECs. As a result of our findings, we suggest that TMAO might be a potential therapeutic target for CKD-associated vascular aging. Blocking the GATA4 pathway may offer a therapeutic approach.