SDF-1/CXCR4轴通过NF-κb信号通路调控炎症反应减轻动脉粥样硬化的形成

周明, 汪家文, 路艳林, 彭进, 丁九阳, 乐翠云, 李芳琴, 王杰, 刘玉波, 夏冰

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重庆医科大学学报 ›› 2025, Vol. 50 ›› Issue (02) : 237-243. DOI: 10.13406/j.cnki.cyxb..003655
基础研究

SDF-1/CXCR4轴通过NF-κb信号通路调控炎症反应减轻动脉粥样硬化的形成

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SDF-1/CXCR4 axis regulates inflammatory responses to attenuate atherosclerosis via the NF-κb signaling pathway

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摘要

目的 确定基质细胞衍生因子-1/趋化因子受体4（stromal cell-derived factor-1/C-X-C chemokine receptor 4，SDF-1/CXCR4）信号轴如何在动脉粥样硬化中发挥作用，并探讨其相关的分子机制。 方法 将40只载脂蛋白E-/-小鼠分为5组：对照组（control group，CON）、高脂饲料组（high-fat diet，HFD）、空载病毒组（adeno-associated virus 9 enhanced green fluorescent protein，AAV9-eGFP）、病毒敲减组（adeno-associated virus 9-CXCR4-small interfering RNA，AAV9-CXCR4-siRNA）和吡咯烷二硫代氨基甲酸酯（pyrrolidine dithiocarbamate，PDTC）组。CON组普通饲料喂养，其余4 组高脂饲料喂养16周。PDTC组从第五周开始腹腔注射60 mg/kg PDTC，2次/周。12周时，AAV9-CXCR4-siRNA组和AAV9-eGFP组分别接受尾静脉注射rAAV9-CXCR4-RNAi和阴性对照病毒，HFD组注射等量生理盐水。使用共聚焦荧光显微镜测定增强型绿色荧光蛋白（enhanced green fluorescent protein，eGFP）的表达，采用苏木精-伊红染色（hematoxylin-eosin，HE）染色法显示动脉粥样硬化斑块的面积，免疫组织化学（immunohistochemistry，IHC）染色和免疫印迹法（Western blot，WB）检测CXCR4、核因子-κB p65（nuclear factor kappaB p65，NF-κB p65）、磷酸化核因子-κB p65（nuclear factor kappaB p-p65，NF-κB p-p65）、白细胞介素-1β（interleukin-1β，IL-1β）和肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）。 结果 HE染色显示，与CON组相比，各组均出现动脉粥样硬化斑块，AAV9-CXCR4-siRNA组的斑块小于AAV9-eGFP组。与HFD组相比，PDTC组的斑块更小。此外，与HFD组相比，PDTC组的血清中SDF-1、IL-1β和TNF-α水平较低；与AAV9-eGFP组相比，PDTC组的SDF-1、IL-1β和TNF-α血清水平更低。IHC结果显示，与CON组相比，CXCR4和SDF-1在HFD组和AAV9-eGFP组中高表达。然而，AAV9-CXCR4-siRNA组与AAV9-eGFP组相比，斑块区域的CXCR4（F=9.621，P=0.000）和SDF-1（F=20.102，P=0.000）表达减少。此外，WB实验表明，与HFD组相比，PDTC 组的 SDF-1（F=54.093，P=0.000）和CXCR4（F=28.485，P=0.000）表达降低。与AAV9-eGFP组相比，AAV9-CXCR4-siRNA组的SDF-1和CXCR4表达量较低（F=9.621，P=0.000；F=20.102，P=0.000）。Pearson相关分析表明，CXCR4与NF-κb p65（r=0.762，P=0.000）、NF-κb p-p65（r=0.795，P=0.000）、白细胞介素-1（interleukin-1，IL-1）（r=0.786，P=0.000）、TNF-α（r=0.844，P=0.000）和SDF-1（r=0.815，P=0.000）蛋白水平呈正相关。 结论 抑制SDF-1/CXCR4轴可通过NF-κb信号通路降低炎症反应，从而减轻动脉粥样硬化的发生发展。

Abstract

Objective To determine the role of stromal cell-derived factor-1/C-X-C chemokine receptor 4（SDF-1/CXCR4） signaling axis in atherosclerosis and to investigate its associated molecular mechanisms. Methods Forty ApoE-/- mice were divided into five groups：control（CON） group，high-fat diet（HFD） group，empty virus（adeno-associated virus 9 enhanced green fluorescent protein，AAV9-eGFP） group，virus knockdown（adeno-associated virus 9-CXCR4-small interfering RNA，AAV9-CXCR4-siRNA） group，and pyrrolidine dithiocarbamate（PDTC） group. The CON group was fed normal chow and the remaining four groups were fed high-fat chow for 16 weeks. The PDTC group received intraperitoneal injections of 60 mg/kg PDTC twice/week starting from the fifth week. At 12 weeks，the AAV9-CXCR4-siRNA group and the AAV9-eGFP group received tail-vein injection of rAAV9-CXCR4-RNAi and negative control viruses，respectively，while the HFD group was injected with an equal amount of physiologic saline. The expression of enhanced green fluorescent protein（eGFP） was determined using confocal fluorescence microscopy. The area of atherosclerotic plaques was visualized by hematoxylin and eosin staining. Immunohistochemical staining and Western blot were used to detect the expression of CXCR4，nuclear factor kappa B p65 （NF-κB p65），phosphorylated nuclear factor-κB p65（NF-κB p-p65），interleukin-1β（IL-1β），and tumor necrosis factor-α（TNF-α）. Results Hematoxylin and eosin staining showed that atherosclerotic plaques were clearly present in all groups except the CON group，and plaques in the AAV9-CXCR4-siRNA group were significantly smaller than those in the AAV9-eGFP group. Plaques were significantly smaller in the PDTC group compared with the HFD group. In addition，the serum levels of SDF-1，IL-1β，and TNF-α were lower in the PDTC group compared with the HFD group. The serum levels of SDF-1，IL-1β，and TNF-α were lower in the PDTC group compared with the AAV9-eGFP group. Immunohistochemical staining showed that the expression levels of CXCR4 and SDF-1 were higher in the HFD and AAV9-eGFP groups than in the CON group. However，the expression levels of CXCR4（F=9.621，P=0.000） and SDF-1（F=20.102，P=0.000） were significantly reduced in the plaque region in the AAV9-CXCR4-siRNA group compared with the AAV9-eGFP group. In addition，Western blot showed that the expression levels of SDF-1（F=54.093，P=0.000） and CXCR4（F=28.485，P=0.000） were significantly reduced in the PDTC group compared with the HFD group. SDF-1 and CXCR4 expression levels were significantly lower in the AAV9-CXCR4-siRNA group compared with the AAV9-eGFP group（F=9.621，P=0.000；F=20.102，P=0.000）. Pearson correlation analysis showed that CXCR4 was positively correlated with the protein levels of NF-κb p65（r=0.762，P=0.000），NF-κb p-p65（r=0.795，P=0.000），IL-1（r=0.786，P=0.000），TNF-α（r=0.844，P=0.000），and SDF-1（r=0.815，P=0.000）. Conclusion Inhibition of the SDF-1/CXCR4 axis reduces the inflammatory response through the NF-κb signaling pathway，thereby attenuating the development and progression of atherosclerosis.

关键词

趋化因子配体12/趋化因子受体4信号轴 / 动脉粥样硬化 / 核因子-κB信号通路 / 炎症反应

Key words

C-X-C motif chemokine ligand 12/C-X-C chemokine receptor 4 axis / atherosclerosis / NF-κb signaling pathway / inflammatory response

中图分类号

R543.5 / R363.2

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周明 , 汪家文 , 路艳林 , 等. SDF-1/CXCR4轴通过NF-κb信号通路调控炎症反应减轻动脉粥样硬化的形成. 重庆医科大学学报. 2025, 50(02): 237-243 https://doi.org/10.13406/j.cnki.cyxb..003655
Zhou Ming, Wang Jiawen, Lu Yanlin, et al. SDF-1/CXCR4 axis regulates inflammatory responses to attenuate atherosclerosis via the NF-κb signaling pathway[J]. Journal of Chongqing Medical University. 2025, 50(02): 237-243 https://doi.org/10.13406/j.cnki.cyxb..003655

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基金

国家自然科学基金资助项目(82060340)
贵州省科技计划资助项目(黔科合基础-ZK[2021]一般487)
贵州省基础研究计划项目(黔科合基础-ZK[2023]一般330)
贵州省普通高等学校青年科技人才成长项目(黔教合KY字[2021]157)

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