NCOR1 Deficiency in Macrophages Aggravates Aortic Aneurysm Formation via the ANGPTL4-ALDOA-MMP2 Axis

An aortic aneurysm (AA) is a life-threatening cardiovascular condition characterized by progressive aortic dilation and potential rupture. In this study, we determined the function of nuclear receptor corepressor 1 (NCOR1) in macrophages in AA development. First, macrophage-specific NCOR1 knockout (MNKO) mice were generated, followed by treatment with β-aminopropionitrile to induce AA. AA formation was exacerbated in MNKO mice, with increased aortic dilation, elastin degradation, and inflammatory cell infiltration. Furthermore, NCOR1 deficiency promoted M1 macrophage polarization and upregulated the expression of proinflammatory cytokines and matrix metalloproteinases (MMPs). Mechanistically, NCOR1 regulates the ANGPTL4-ALDOA-MMP2 signaling axis in macrophages. Particularly, NCOR1 directly binds to the ANGPTL4 promoter, suppressing its transcription. ANGPTL4 knockdown attenuates NCOR1 deficiency-induced ALDOA and MMP2 upregulation. These findings suggest that macrophage-specific NCOR1 deficiency exacerbates AA formation via enhanced inflammatory responses and extracellular matrix degradation. The identification of the NCOR1-ANGPTL4-ALDOA-MMP2 axis provides new insights into the molecular mechanisms underlying AA development and highlights the essential role of epigenetic regulation in maintaining aortic wall integrity. This discovery may serve as therapeutic targets for preventing and treating AA.