Liu Yandong, Hu Weilin, Yang Futang, Zou Sili, Ren Huiqiong, Zuo Yong, Qu Lefeng
Department of Geriatrics, 905, Hospital of PLA NAVY, Shanghai, China.
Department of Vascular and Endovascular Surgery, Changzheng Hospital, Affiliated to the Naval Medical University, Shanghai, 200003, China.
J Cardiovasc Transl Res. 2025 Feb;18(1):3-16. doi: 10.1007/s12265-024-10576-w. Epub 2025 Jan 15.
CHI3L1 is strongly associated with atherosclerosis, but its role in macrophages remains unknown. In this study, we observed a significant up-regulation of CHI3L1 in both carotid plaques and serum of symptomatic patients, and demonstrated that CHI3L1 impairs the efferocytosis of macrophages by down-regulating crucial efferocytic mediator MFGE8 through inhibiting ATF2, which binds directly to the enhancer of MFGE8. In human plaques, we observed a negative correlation between CHI3L1 expression and both ATF2 and MFGE8 levels, further proved their involvement in plaque destabilization. Using Ldlr-/- mice with tandem carotid stenosis surgery, we demonstrated that administration of CHI3L1 protein resulted in enlarged atherosclerotic necrotic cores and decreased MFGE8 and ATF2 levels. Conversely, treatment with a CHI3L1 blocking antibody exhibited the opposite trend.In conclusion, CHI3L1 destabilizes atherosclerotic plaque by impairing macrophagic efferocytosis through the down-regulation of ATF2-induced MFGE8 expression. Targeting CHI3L1 may offer a promising therapeutic strategy for the treatment of atherosclerosis.
几丁质酶3样蛋白1（CHI3L1）与动脉粥样硬化密切相关，但其在巨噬细胞中的作用尚不清楚。在本研究中，我们观察到有症状患者的颈动脉斑块和血清中CHI3L1均显著上调，并证明CHI3L1通过抑制直接结合到牛奶脂肪球表皮生长因子8（MFGE8）增强子的活化转录因子2（ATF2），下调关键的胞葬作用介质MFGE8，从而损害巨噬细胞的胞葬作用。在人类斑块中，我们观察到CHI3L1表达与ATF2和MFGE8水平均呈负相关，进一步证明它们参与了斑块的不稳定。使用串联颈动脉狭窄手术的载脂蛋白E基因敲除（Ldlr-/-）小鼠，我们证明给予CHI3L1蛋白会导致动脉粥样硬化坏死核心增大，MFGE8和ATF2水平降低。相反，用CHI3L1阻断抗体治疗则呈现相反的趋势。总之，CHI3L1通过下调ATF2诱导的MFGE8表达损害巨噬细胞胞葬作用，从而使动脉粥样硬化斑块不稳定。靶向CHI3L1可能为动脉粥样硬化的治疗提供一种有前景的治疗策略。
