Sun Jingzhao, Wang Mengqi, Jia Fengming, Song Jiantao, Ren Jinlin, Hu Bo
Department of Emergency, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, People's Republic of China.
Department of Emergency, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China.
J Inflamm Res. 2024 Mar 20;17:1857-1871. doi: 10.2147/JIR.S447379. eCollection 2024.
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.
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.
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.
FTO inhibits VSMC senescence and subsequently slows the progression of atherosclerotic plaques by stabilizing the MIS12 protein.
动脉粥样硬化是动脉粥样硬化性心血管疾病（CVD）的主要原因。在此，我们旨在揭示脂肪量和肥胖相关基因（FTO）在动脉粥样硬化斑块中血管平滑肌细胞（VSMC）衰老调控中的作用及机制。
使用喂食高脂饮食（HFD）的载脂蛋白E（ApoE）小鼠建立动脉粥样硬化动物模型。进行免疫组织化学以及苏木精 - 伊红、油红O、天狼星红和Masson染色，以在体内证实FTO在动脉粥样硬化中的作用。随后，上调或下调原代VSMC中FTO的表达。用氧化低密度脂蛋白（ox-LDL）处理VSMC，然后进行EdU染色、流式细胞术、衰老相关β-半乳糖苷酶（SA-β-gal）染色、免疫荧光、端粒检测、RT-qPCR和蛋白质印迹，以确定FTO抑制VSMC衰老的分子机制。
在喂食HFD的ApoE小鼠的进展性动脉粥样硬化斑块中观察到FTO表达降低。FTO上调可抑制小鼠的动脉粥样硬化病变。FTO通过帮助VSMC抵抗ox-LDL诱导的细胞周期停滞和衰老来抑制动脉粥样硬化斑块中的VSMC衰老。这个过程是通过蛋白酶体介导的途径稳定VSMC中的MIS12蛋白来实现的。
FTO通过稳定MIS12蛋白来抑制VSMC衰老，进而减缓动脉粥样硬化斑块的进展。
