Akkermansia muciniphila alleviates abdominal aortic aneurysms via restoring CITED2 activated by EPAS1.

ABSTRACT

Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease that has been linked to gut microbiome dysbiosis. Therefore, this study aims to investigate the effects of Akkermansia muciniphila (Am) on AAA mice and the biomolecules involved. AAA mice were generated using angiotensin II (Ang II), and 16sRNA sequencing was used to identify an altered abundance of microbiota in the feces of AAA mice. Vascular smooth muscle cell (VSMC) markers and apoptosis, and macrophage infiltration in mouse aortic tissues were examined. The abundance of Am was reduced in AAA mouse feces, and endothelial PAS domain-containing protein 1 (EPAS1) was downregulated in AAA mice and VSMC induced with Ang II. Am delayed AAA progression in mice, which was blunted by knockdown of EPAS1. EPAS1 was bound to the Cbp/p300-interacting transactivator 2 (CITED2) promoter and promoted CITED2 transcription. CITED2 reduced VSMC apoptosis and delayed AAA progression. Moreover, EPAS1 inhibited macrophage inflammatory response by promoting CITED2 transcription. In conclusion, gut microbiome dysbiosis in AAA induces EPAS1-mediated dysregulation of CITED2 to promote macrophage inflammatory response and VSMC apoptosis.