SIRT2 Delays Vulnerable Plaque Progression by Modulating Vascular Smooth Muscle Cell Senescence

The rupture of vulnerable plaques (VPs) serves as the pathophysiological foundation for the occurrence of acute coronary syndrome (ACS). The senescence of vascular smooth muscle cells (VSMCs) is pivotal in the formation and even rupture of VPs. Although previous studies have demonstrated that Sirt2 contributes to the attenuation of vascular aging, its specific mechanisms in VSMC senescence and vulnerable plaque formation remain poorly understood. This study aimed to explore the underlying mechanism of Sirt2 in the formation of vulnerable plaques. Male ApoE^-/- mice were randomly divided into three groups and administered normal saline, empty vector AAV9, or VSMC-specific Sirt2-overexpressing AAV9 via tail vein injection, respectively. Four weeks after viral infection, a mouse model of vulnerable carotid plaques was established by partial ligation of the left carotid artery combined with 8 weeks of high-fat diet feeding. We found that VSMC-specific Sirt2 overexpression significantly delayed VSMC senescence and VP formation. Furthermore, after Sirt2 overexpression, the phosphorylation levels of AMPK and FOXO3a in VSMCs were increased considerably. In vitro further verified that Sirt2 reverses H₂O₂-induced VSMC senescence via the AMPK/FOXO3a pathway. Additionally, using resveratrol, we demonstrated that its protective effects against VSMC senescence are mediated through the Sirt2-AMPK-FOXO3a axis. In conclusion, our experimental data suggest that Sirt2 delays VSMC senescence potentially through the AMPK/FOXO3a pathway, thereby attenuating VPs formation. This study highlights Sirt2 as a potential therapeutic target, and pharmacological activation of Sirt2 may represent a promising strategy for delaying VPs formation and preventing ACS.