Untargeted metabolomics identifies indole-3-propionic acid to relieve Ang II-induced endothelial dysfunction in...

Indole-3-propionic acid (IPA), a gut microbiota-derived metabolite of tryptophan, has been proven to fulfill an essential function in cardiovascular disease (CVD) and nerve regeneration disease. However, the role of IPA in aortic dissection (AD) has not been revealed. We aimed to investigate the role of IPA in the pathogenesis of AD and the underlying mechanisms of IPA in endothelial dysfunction. Untargeted metabolomics has been employed to screen the plasma metabolic profile of AD patients in comparison with healthy individuals. Network pharmacology provides insights into the potential molecular mechanisms underlying IPA. 3-aminopropionitrile fumarate (BAPN) and angiotensin II (Ang II) were administered to induce AD in mice, while human umbilical vein endothelial cells (HUVECs) were employed for in vitro validation of the signaling pathways predicted by network pharmacology. A total of 224 potentially differential plasma metabolites were identified in the AD patients, with 110 up-regulated metabolites and 114 down-regulated metabolites. IPA was the most significantly decreased metabolite involved in tryptophan metabolism. Bcl2, caspase3, and AKT1 were predicted as the target genes of IPA by network pharmacology and molecular docking. IPA suppressed Ang II-induced apoptosis, intracellular ROS generation, inflammation, and endothelial tight junction (TJ) loss. Animal experiments demonstrated that administration of IPA alleviated the occurrence and severity of AD in mice. Taken together, we identified a previously unexplored association between tryptophan metabolite IPA and AD, providing a novel perspective on the underlying mechanism through which IPA mitigates endothelial dysfunction to protect against AD.