Deacetylation of SRF catalyzed by SIRT7 protects against abdominal aortic aneurysm formation.

Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease for which no effective pharmacological treatments exist. Histone deacetylases (HDACs) have emerged as critical regulators of cardiovascular pathophysiology; however, the contributions of individual HDAC isoforms to AAA formation remain largely undefined. Here, we identified sirtuin 7 (SIRT7) as the most markedly downregulation isoform among 18 HDAC family members in human AAA tissues. Global and vascular smooth muscle cell (VSMC)-specific Sirt7 knockout exacerbated AAA formation, whereas SIRT7 overexpression attenuated aneurysm progression. Mechanistically, SIRT7 deacetylates serum response factor (SRF) at lysine 154, thereby preventing SRF nuclear-to-cytoplasmic translocation and ubiquitin-mediated degradation and preserving the VSMC contractile phenotype. Consequently, SIRT7 deficiency enhances SRF acetylation, accelerates its degradation, and promotes VSMC phenotypic switching, ultimately facilitating AAA progression. Pharmacological activation of SIRT7 with the NAD⁺ precursor nicotinamide mononucleotide attenuated aortic dilation. Collectively, our findings reveal a crucial role for SIRT7-mediated SRF-K154 deacetylation in limiting AAA progression and suggest that nicotinamide mononucleotide supplementation may represent a promising therapeutic strategy for AAA.