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

Zhou Ming, Wang Jiawen, Lu Yanlin, Peng Jin, Ding Jiuyang, Le Cuiyun, Li Fangqin, Wang Jie, Liu Yubo, Xia Bing

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Journal of Chongqing Medical University ›› 2025, Vol. 50 ›› Issue (02) : 237-243. DOI: 10.13406/j.cnki.cyxb..003655
Basic research

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

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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.

Key words

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

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Zhou Ming , Wang Jiawen , Lu Yanlin , et al . SDF-1/CXCR4 axis regulates inflammatory responses to attenuate atherosclerosis via the NF-κb signaling pathway. Journal of Chongqing Medical University. 2025, 50(02): 237-243 https://doi.org/10.13406/j.cnki.cyxb..003655

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