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Published on: September 26, 2018
Aminoadipic acid aggravates atherosclerotic vascular inflammation through ROS/TXNIP/NLRP3 pathway, a harmful
Tian Wang1, Hongfei Wu2, Xiaoyan Shi2
1Department of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China.
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.
Insights
Aminoadipic acid (AAA) promotes atherosclerosis (AS) vascular inflammation by activating the ROS/TXNIP/NLRP3 pathway. Paeonol (Pae) inhibits AS by reducing AAA levels via gut microbiota, offering a new treatment strategy.
Area of Science:
- Biochemistry
- Microbiology
- Cardiovascular Research
Background:
- A previous study identified aminoadipic acid (AAA) as a differential microbial metabolite in atherosclerosis (AS) mice, suspected to be harmful.
- The precise role of AAA in promoting AS vascular inflammation and its underlying mechanisms remained unclear.
- Paeonol (Pae) is known to have an anti-AS role, but its effect on serum AAA levels and its mechanism were not understood.
Purpose of the Study:
- To investigate whether aminoadipic acid (AAA) promotes AS vascular inflammation and elucidate its mechanisms.
- To determine if Paeonol (Pae) exerts its antiatherogenic effects by reducing serum AAA levels.
- To explore the role of gut microbiota in Pae's effect on AAA and AS.
Main Methods:
- Clinical analysis of serum AAA levels in AS patients versus healthy individuals.
- In vivo studies using AS mice supplemented with AAA or treated with Pae.
- In vitro studies stimulating human umbilical vein endothelial cells (HUVECs) with AAA.
- Assessment of aortic plaque size, lipid profiles, inflammatory cytokines, oxidative stress markers (ROS, malondialdehyde), and protein levels (ASC, TXNIP, NLRP3, caspase-1).
- Microbiota manipulation using broad-spectrum antibiotics and fecal microbiota transplantation.
Main Results:
- AS patients exhibited higher serum AAA levels than healthy controls.
- AAA supplementation exacerbated AS, increasing plaque size and inflammation.
- AAA stimulation in HUVECs increased ROS and activated the NLRP3 inflammasome pathway, effects reversed by NAC and a NLRP3 inhibitor.
- Pae treatment reduced AS plaque size, improved lipid profiles, and decreased inflammation in AS mice.
- Pae lowered serum AAA levels in AS mice via gut microbiota transmission and inhibited aortic NLRP3 inflammasome activation.
- Antibiotics diminished Pae's inhibitory effect on NLRP3 inflammasome.
Conclusions:
- Aminoadipic acid (AAA) promotes AS vascular inflammation by activating the ROS/TXNIP/NLRP3 pathway.
- Paeonol (Pae) inhibits AS development by reducing serum AAA levels in a microbiota-dependent manner.
- AAA may serve as a potential biomarker for AS diagnosis, and Pae represents a novel therapeutic strategy for AS.
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