Indole-3-propionic acid attenuates aortic dissection by inhibiting neutrophil extracellular traps via the...

Aortic dissection (AD) is a life-threatening cardiovascular emergency, and its pathological progression is accompanied by metabolic dysregulation. This study aimed to investigate the role and underlying mechanisms of metabolic dysregulation in the progression of AD. Through metabolomic analysis of serum from clinical AD patients and a β-aminopropionitrile (BAPN) induced animal model, we found that indole-3-propionic acid (IPA), a tryptophan metabolite, was significantly decreased in AD. in vivo experiments demonstrated that IPA supplementation significantly reduced mortality and aortic injury in AD mice. Tissue transcriptomics combined with in vivo and in vitro experiments further revealed that the vascular protective effects of IPA primarily depend on the inhibition of neutrophil extracellular traps (NETs) release. Mechanistically, IPA activates the aryl hydrocarbon receptor (AHR) in neutrophils, driving the nuclear translocation of the downstream antioxidant regulator Nrf2. This process reduces intracellular reactive oxygen species (ROS) levels, ultimately suppressing NETs formation. The use of AHR knockout models and pharmacological inhibition of Nrf2 further validated that the anti-AD effects of IPA are dependent on the AHR/Nrf2/ROS signaling axis. In conclusion, our study identifies IPA reduction as a key metabolic characteristic of AD and suggests that IPA supplementation may serve as a novel therapeutic strategy for the prevention and treatment of AD.