Resveratrol suppresses GATA4/Sortilin pathway to attenuate vascular smooth muscle cell senescence-associated secretory phenotype and vascular aging-related atherosclerosis.

This study aimed to investigate the role of Sortilin in vascular smooth muscle cell (VSMC) senescence(definition) and the senescence-associated secretory phenotype (SASP) and to explore whether GATA4 promotes VSMC senescence and aortic atherosclerosis by transcriptionally regulating Sortilin. Furthermore, we examined the potential of resveratrol (Res) to alleviate vascular aging and atherogenesis via the GATA4/Sortilin pathway. Bioinformatics analysis and experimental validation revealed co-upregulation of GATA4 and Sortilin in senescent VSMCs. Sortilin overexpression promoted VSMC senescence and SASP secretion, whereas its silencing resulted in the opposite effects. GATA4 transcriptionally activated Sortilin expression via direct binding to the Sort1 promoter, as confirmed by dual-luciferase reporter and chromatin immunoprecipitation (ChIP)-qPCR assays. Although GATA4-induced VSMC senescence was enhanced by co-overexpression of Sortilin, Sortilin knockdown did not significantly reverse GATA4-driven senescence, suggesting the involvement of additional mechanisms. Res treatment suppressed GATA4 and Sortilin expression, thereby attenuating VSMC senescence and the SASP. In apolipoprotein E-deficient (ApoE^-/-) mice fed a high-fat diet, AAV-mediated GATA4 overexpression promoted Sortilin expression, vascular oxidative stress, inflammation and accelerated aortic aging and atherosclerosis. These effects were counteracted by either AAV-Sortilin shRNA or dietary Res supplementation, which also improved blood lipid and glucose metabolism. In summary, GATA4 transcriptionally upregulates Sortilin expression, thereby promoting VSMC senescence and vascular aging. Res inhibits the GATA4/Sortilin pathway, suggesting a potential therapeutic strategy for ameliorating atherosclerosis.