Aminoadipic acid aggravates atherosclerotic vascular inflammation through ROS/TXNIP/NLRP3 pathway, a harmful microbial metabolite reduced by paeonol

Aim

Our previous study has found a differential microbial metabolite in atherosclerosis (AS) mice, aminoadipic acid (AAA), which was considered as a potential harmful metabolite. However, whether it can promote AS vascular inflammation and its mechanisms remain unclear. Paeonol (Pae) plays an anti-AS role by regulating the metabolic profile, but whether Pae exerts its antiatherogenic effect by reducing serum AAA levels is unknown.

Results

The clinical trial results showed that the AS patients’ serum AAA levels were higher than those healthy people’. Besides, AAA supplementation could increase aortic plaque size, serum inflammatory cytokines levels and liver malondialdehyde, superoxide dismutase levels in AS mice. Moreover, after AAA stimulation, the ROS levels and ASC, TXNIP, NLRP3 and caspase-1 proteins levels were increased in HUVECs, which could be reversed by antioxidant NAC and NLRP3 inhibitor. Pae significantly reduced the plaque size in the aorta, improved blood lipid levels and decreased serum inflammation factor levels in AS mice. Simultaneously, Pae could reduce the serum AAA levels of AS mice through the gut microbiota transmission. Finally, Pae inhibited NLRP3 inflammasome activation in aortas of AS mice. Broad-spectrum antibiotics could weaken the inhibitory effect of Pae on NLRP3 inflammasome.

Conclusion

Our study clarified that AAA could promote AS vascular inflammation via activating the ROS/TXNIP/NLRP3 pathway. Pae could inhibit AS development by reducing serum AAA levels in a microbiota-dependent manner. Taken together, we proposed that AAA could be served as a potential biomarker for AS clinical diagnosis and provided a new treatment strategy for AS.