Trimethylamine N-oxide promotes abdominal aortic aneurysm by inducing vascular inflammation and vascular smooth muscle cell phenotypic switching

• Published in: European journal of pharmacology Vol. 965; p. 176307
• Main Authors: Wei, Bo, Deng, Na, Guo, Haijun, Wei, Yingying, Xu, Fujia, Luo, Sihan, You, Weili, Chen, Jingjing, Li, Wei, Si, Xiaoyun
• Format: Journal Article
• Language: English
• Published: Netherlands 15-02-2024
• Subjects: Vascular smooth muscle cell; Inflammation; Trimethylamine N-Oxide; Nuclear factor-κB signaling; Aortic aneurysm; Macrophage
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2023.176307

Inflammation and vascular smooth muscle cell (VSMC) phenotypic switching are implicated in the pathogenesis of abdominal aortic aneurysm (AAA). Trimethylamine N-oxide (TMAO) has emerged as a crucial risk factor in cardiovascular diseases, inducing vascular inflammation and calcification. We aimed to evaluate the effect of TMAO on the formation of AAA.
Here, we showed that TMAO was elevated in plasma from AAA patients compared with nonaneurysmal subjects by liquid chromatography‒mass spectrometry (LC‒MS) detection. Functional studies revealed that increased TMAO induced by feeding a choline-supplemented diet promoted Ang II-induced AAA formation. Immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and Western blot analyses revealed that TMAO induced macrophage infiltration and inflammatory factor release. Conversely, inhibition of TMAO by supplementation with DMB suppressed AAA formation and the inflammatory response. Molecular studies revealed that TMAO regulated VSMC phenotypic switching. Flow cytometry analyses showed that TMAO induces macrophage M1-type polarization. Furthermore, pharmacological intervention experiments suggested that the nuclear factor-κB (NF-κB) signaling pathway was critical for TMAO to trigger AAA formation.
TMAO promotes AAA formation by inducing vascular inflammation and VSMC phenotypic switching through activation of the NF-κB signaling pathway. Thus, TMAO is a prospective therapeutic AAA target.