FTO Stabilizes MIS12 to Inhibit Vascular Smooth Muscle Cell Senescence in Atherosclerotic Plaque

Purpose: Atherosclerosis is the main cause of atherosclerotic cardiovascular disease (CVD).Here, we aimed to uncover the role and mechanisms of fat mass and obesity-associated genes (FTO) in the regulation of vascular smooth muscle cell (VSMC) senescence in atherosclerotic plaques.Methods: ApoE -/-mice fed a high-fat diet (HFD) were used to establish an atherosclerotic animal model.Immunohistochemistry, and the staining of hematoxylin-eosin, Oil Red O, Sirius red, and Masson were performed to confirm the role of FTO in atherosclerosis in vivo.Subsequently, FTO expression in primary VSMCs is either upregulated or downregulated.Oxidized low-density lipoprotein (ox-LDL) was used to treat VSMCs, followed by EdU staining, flow cytometry, senescence-associated β-galactosidase (SA-β-gal) staining, immunofluorescence, telomere detection, RT-qPCR, and Western blotting to determine the molecular mechanisms by which FTO inhibits VSMC senescence.Results: Decreased FTO expression was observed in progressive atherosclerotic plaques of ApoE -/-mice fed with HFD.FTO upregulation inhibits atherosclerotic lesions in mice.FTO inhibits VSMC aging in atherosclerotic plaques by helping VSMC withstand ox-LDL-induced cell cycle arrest and senescence.This process is achieved by stabilizing the MIS12 protein in VSMC through a proteasome-mediated pathway.Conclusion: FTO inhibits VSMC senescence and subsequently slows the progression of atherosclerotic plaques by stabilizing the MIS12 protein.