Work

5-Azacytidine suppresses the incidence of abdominal aortic aneurysm through the epigenetic regulation of macrophage polarization

Year: 2026

Type: article

Abstract: Objective: Abdominal aortic aneurysm (AAA) is a life-threatening disease characterized by chronic vascular inflammation and extracellular matrix degradation. Macrophage polarization and epigenetic regulation via DNA methylation contribute to AAA pathogenesis. This study aimed to investigate the effects of DNA methyltransferase 1 (DNMT1) inhibitor 5-azacytidine (5-aza) on AAA development and its underlying mechanisms. Methods: Apolipoprotein E knockout mice were infused with angiotensin II (Ang II) to induce AAA formation and treated with 5-aza or left untreated. Histological and immunohistochemical analyses were performed to evaluate DNA methylation status and macrophage phenotype. In vitro, RAW 264.7 macrophages were stimulated with Ang II with or without 5-aza, followed by immunostaining, reverse transcription quantitative polymerase chain reaction, and Western blotting. DNMT1 was silenced using small-interfering RNA. Promoter methylation status was evaluated by methylation-specific polymerase chain reaction. Publicly available bulk microarray datasets were analyzed to support the experimental findings. Results: promoter in vivo and in vitro, which was associated with increased PPARγ expression and a reduced M1/M2 macrophage ratio. Conclusions: promoter methylation. Targeting DNA methylation represents a potential therapeutic strategy for AAA. Clinical relevance: There is currently no established pharmacological therapy for abdominal aortic aneurysm (AAA). We demonstrate that DNA methyltransferase 1 inhibition by 5-azacytidine suppresses AAA formation by reducing DNA methylation and the M1/M2 macrophage ratio via upregulation of peroxisome proliferator-activated receptor γ expression. These findings identify epigenetic regulation as a key mechanism in AAA pathogenesis. Given that 5-azacytidine is already clinically available, targeting DNA methylation may represent a potential translational strategy to inhibit AAA formation, although optimization of dosing and safety will be required.

Source: JVS Vascular Science

DOI: 10.1016/j.jvssci.2026.100447