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Knockdown of GBP5 Attenuates Abdominal Aortic Aneurysm Formation via the NF-κB Pathway.

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Τίτλος: Knockdown of GBP5 Attenuates Abdominal Aortic Aneurysm Formation via the NF-κB Pathway.
Συγγραφείς: Wang Y; Department of Cardiac Surgery, Shandong Provincial Third Hospital, Shandong University, No. 11 Wuyingshan Middle Road, Tianqiao District, Jinan, 250031, Shandong, China., Wang J; Department of Cardiac Surgery, Shandong Provincial Third Hospital, Shandong University, No. 11 Wuyingshan Middle Road, Tianqiao District, Jinan, 250031, Shandong, China., Chang Z; Department of Cardiac Surgery, Shandong Provincial Third Hospital, Shandong University, No. 11 Wuyingshan Middle Road, Tianqiao District, Jinan, 250031, Shandong, China. 153119434@qq.com.
Πηγή: Applied biochemistry and biotechnology [Appl Biochem Biotechnol] 2026 Jul; Vol. 198 (7), pp. 5293-5308. Date of Electronic Publication: 2026 Apr 17.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Humana Press Country of Publication: United States NLM ID: 8208561 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-0291 (Electronic) Linking ISSN: 02732289 NLM ISO Abbreviation: Appl Biochem Biotechnol Subsets: MEDLINE
Imprint Name(s): Original Publication: Clifton, N.J. : Humana Press, c1981-
Ιατρικοί όροι (MeSH): Aortic Aneurysm, Abdominal*/metabolism , Aortic Aneurysm, Abdominal*/pathology , Aortic Aneurysm, Abdominal*/genetics , Aortic Aneurysm, Abdominal*/chemically induced , NF-kappa B*/metabolism , GTP-Binding Proteins*/genetics , GTP-Binding Proteins*/metabolism , Signal Transduction* , Gene Knockdown Techniques*, Angiotensin II/pharmacology ; Myocytes, Smooth Muscle/metabolism ; Myocytes, Smooth Muscle/pathology ; Toll-Like Receptor 4/metabolism ; Muscle, Smooth, Vascular/metabolism ; Muscle, Smooth, Vascular/pathology ; Animals ; Mice ; RAW 264.7 Cells ; Male ; Mice, Inbred C57BL
Περίληψη: Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease associated with high mortality rates upon rupture. Guanylate binding protein 5 (GBP5) has been implicated in the exacerbation of inflammatory responses in various diseases, including rosacea, osteoarthritis, and lupus nephritis. However, its role in the development and progression of AAA remains unclear. This study aimed to investigate the role of GBP5 in the development and progression of AAA. An angiotensin II (Ang II)-infused ApoE−/− mice, LPS-treated Raw 264.7 cells, and a Raw 264.7 and vascular smooth muscle cells (VSMCs) co-culture system were used to investigate the role of GBP5 in AAA progression. The effects of GBP5 knockdown on AAA were determined using histological assessments, immunohistochemistry, immunofluorescence, western blot, ELISA, and RT-qPCR experiments. GBP5 expression was upregulated in the aorta of Ang II-treated mice. Knockdown of GBP5 attenuated AAA progression, as evidenced by the reduced aortic diameter and preserved elastin integrity. GBP5 knockdown reduced inflammation and suppressed VSMC phenotypic switching in Ang II-induced mice. Mechanistically, GBP5 knockdown reversed Ang II-induced upregulation of TLR4 and p-NF-κB p65 levels in mouse aortas. In vitro, GBP5 silencing attenuated LPS-induced M1 macrophage polarization by modulating the TLR4/NF-κB pathway. Furthermore, GBP5 knockdown in macrophages inhibited VSMC phenotypic switching in the co-culture system. Our results demonstrated that GBP5 knockdown attenuated AAA progression by reducing reduced inflammation and inhibiting phenotypic switching of VSMCs through inactivation of the TLR4/NF-κB pathway. These results indicated that targeting GBP5 may be a potential therapeutic approach for AAA.
Competing Interests: Declarations. Ethics Approval and Consent to Participate: The experimental protocol of our study was performed in accordance with the Guide for the Care and Use of Laboratory Animals and approved by Shandong Provincial Third Hospital, Shandong University (DWKYLL-2024329). Consent for Publication: Not applicable. Competing interests: The authors declare that they have no conflicts of interest.
References: Haque, K., & Bhargava, P. (2022). Abdominal Aortic Aneurysm. Am Fam Physician, 106(2), 165–172. (PMID: 35977132)
Rustempasic, N., & Semi, S. (2019). Correlation of Atherosclerotic Risk Factors with the Size of Abdominal Aortic Aneurysm (AAA). Mater Sociomed, 31(4), 273–276. (PMID: 10.5455/msm.2019.31.273-276320820927007617)
Regnier, P., Lareyre, F., Hassen-Khodja, R., Durand, M., Touma, J., & Raffort, J. (2018). Sexual Dysfunction After Abdominal Aortic Aneurysm Surgical Repair: Current Knowledge and Future Directions. European Journal Of Vascular And Endovascular Surgery, 55(2), 267–280. (PMID: 10.1016/j.ejvs.2017.11.02829292207)
Golledge, J., Thanigaimani, S., Powell, J. T., & Tsao, P. S. (2023). Pathogenesis and management of abdominal aortic aneurysm. European Heart Journal, 44(29), 2682–2697. (PMID: 10.1093/eurheartj/ehad3863738726010393073)
Lu, H., Du, W., Ren, L., Hamblin, M. H., Becker, R. C., Chen, Y. E., & Fan, Y. (2021). Vascular Smooth Muscle Cells in Aortic Aneurysm: From Genetics to Mechanisms. J Am Heart Assoc, 10(24), 19. (PMID: 10.1161/JAHA.121.023601)
Cai, D., Sun, C., Zhang, G., Que, X., Fujise, K., Weintraub, N. L., & Chen, S. Y. (2021). A Novel Mechanism Underlying Inflammatory Smooth Muscle Phenotype in Abdominal Aortic Aneurysm. Circ Res, 129(10), e202–e214. (PMID: 10.1161/CIRCRESAHA.121.319374345515878575453)
Zhu, J., Meganathan, I., MacAruthur, R., & Kassiri, Z. (2024). Inflammation in Abdominal Aortic Aneurysm: Cause or Comorbidity? Canadian Journal Of Cardiology, 40(12), 2378–2391. (PMID: 10.1016/j.cjca.2024.08.27439181326)
Márquez-Sánchez, A. C., & Koltsova, E. K. (2022). Immune and inflammatory mechanisms of abdominal aortic aneurysm. Frontiers In Immunology, 13, 989933. (PMID: 10.3389/fimmu.2022.989933362757589583679)
Wei, B., Deng, N., Guo, H., Wei, Y., Xu, F., Luo, S., You, W., Chen, J., Li, W., & Si, X. (2024). Trimethylamine N-oxide promotes abdominal aortic aneurysm by inducing vascular inflammation and vascular smooth muscle cell phenotypic switching. European Journal Of Pharmacology, 965(176307), 29.
Hou, N., Zhou, H., Li, J., Xiong, X., Deng, H., & Xiong, S. (2024). Macrophage polarization and metabolic reprogramming in abdominal aortic aneurysm. Immunity Inflammation and Disease, 12(11), e1268.
Luu, L. D. W., Pandey, A., Paramsothy, S., Ngo, C., Castaño-Rodríguez, N., Liu, C., Kamm, M. A., Borody, T. J., Man, S. M., & Kaakoush, N. O. (2024). Profiling the colonic mucosal response to fecal microbiota transplantation identifies a role for GBP5 in colitis in humans and mice. Nature Communications, 15(1), 024–46983. (PMID: 10.1038/s41467-024-46983-5)
Chiu, H. W., Lin, C. H., Lee, H. H., Lu, H. W., Lin, Y. K., Lin, Y. F., & Lee, H. L. (2024). Guanylate binding protein 5 triggers NF-κB activation to foster radioresistance, metastatic progression and PD-L1 expression in oral squamous cell carcinoma. Clin Immunol, 259(109892), 5.
Li, J., Liu, K., He, W., Zhang, W., & Li, Y. (2024). Inhibition of GBP5 activates autophagy to alleviate inflammatory response in LPS-induced lung injury in mice. Experimental Lung Research, 50(1), 106–117. (PMID: 10.1080/01902148.2024.233926938642025)
Tong, Q., Li, D., Yin, Y., Cheng, L., & Ouyang, S. (2023). GBP5 Expression Predicted Prognosis of Immune Checkpoint Inhibitors in Small Cell Lung Cancer and Correlated with Tumor Immune Microenvironment. J Inflamm Res, 16, 4153–4164. (PMID: 10.2147/JIR.S4014303775017010518156)
Tang, H., Gong, X., Dai, J., Gu, J., Dong, Z., Xu, Y., Hu, Z., Zhao, C., Deng, J., & Dong, S. (2023). The IRF1/GBP5 axis promotes osteoarthritis progression by activating chondrocyte pyroptosis. J Orthop Translat, 44, 47–59. (PMID: 10.1016/j.jot.2023.11.0053822966010789940)
Qiu, R., Chen, S., Hua, F., Bian, S., Chen, J., Li, G., & Wu, X. (2021). Betanin Prevents Experimental Abdominal Aortic Aneurysm Progression by Modulating the TLR4/NF-κB and Nrf2/HO-1 Pathways. Biological &/And Pharmaceutical Bulletin, 44(9), 1254–1262. (PMID: 10.1248/bpb.b21-00042)
Dai, M., Zhu, X., Zeng, S., Liu, Q., Hu, R., Huang, L., Wang, Y., Deng, J., & Yu, Q. (2023). Dexmedetomidine protects cells from Angiotensin II-induced smooth muscle cell phenotype switch and endothelial cell dysfunction. Cell Cycle, 22(4), 450–463. (PMID: 10.1080/15384101.2022.212448936196460)
Zhou, L., Zhao, H., Meng, X., Zhao, Z., Xie, H., Li, J., Tang, Y., & Zhang, Y. (2023). GBP5 exacerbates rosacea-like skin inflammation by skewing macrophage polarization towards M1 phenotype through the NF-κB signalling pathway. Journal Of The European Academy Of Dermatology And Venereology, 37(4), 796–809. (PMID: 10.1111/jdv.1872536367676)
Piedrahita, J. A., Zhang, S. H., Hagaman, J. R., Oliver, P. M., & Maeda, N. (1992). Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc Natl Acad Sci U S A, 89(10), 4471–4475. https://doi.org/10.1073/pnas.89.10.4471. (PMID: 10.1073/pnas.89.10.4471158477949104)
Li, J. M., Deng, H. S., Yao, Y. D., Wang, W. T., Hu, J. Q., Dong, Y., Wang, P. X., Liu, L., Liu, Z. Q., Xie, Y., Lu, L. L., & Zhou, H. (2023). Sinomenine ameliorates collagen-induced arthritis in mice by targeting GBP5 and regulating the P2X7 receptor to suppress NLRP3-related signaling pathways. Acta Pharmacologica Sinica, 44(12), 2504–2524. (PMID: 10.1038/s41401-023-01124-43748257010692212)
Yu, X., Jin, J., Zheng, Y., Zhu, H., Xu, H., Ma, J., Lan, Q., Zhuang, Z., Chen, C. C., & Li, M. (2021). GBP5 drives malignancy of glioblastoma via the Src/ERK1/2/MMP3 pathway. Cell Death And Disease, 12(2), 021–03492. (PMID: 10.1038/s41419-021-03492-3)
Zhang, J., Zhang, Y., Chen, Q., Qi, Y., & Zhang, X. (2024). The XPO1 inhibitor selinexor ameliorates bleomycin-induced pulmonary fibrosis in mice via GBP5/NLRP3 inflammasome signaling. International Immunopharmacology, 130(111734), 28.
Feng, J., Cao, Z., Wang, L., Wan, Y., Peng, N., Wang, Q., Chen, X., Zhou, Y., & Zhu, Y. (2017). Inducible GBP5 Mediates the Antiviral Response via Interferon-Related Pathways during Influenza A Virus Infection. Journal Of Innate Immunity, 9(4), 419–435. (PMID: 10.1159/000460294283765016738859)
Zhong, K., Liu, K., Song, Y., Chen, S., Hu, X., Xue, R., Ma, X., Li, S., Yang, J., Deng, Z., Zhu, X., Yuan, M., Huang, Y., Yin, W., Chen, Y., Tang, Y., & Shi, Z. (2023). A Synthetic Steroid 5α-Androst-3β, 5, 6β-triol Alleviates Radiation-Induced Brain Injury in Mice via Inhibiting GBP5/NF-κB/NLRP3 Signal Axis. Molecular Neurobiology, 7(10), 023–03831.
Niestrawska, J. A., Regitnig, P., Viertler, C., Cohnert, T. U., Babu, A. R., & Holzapfel, G. A. (2019). The role of tissue remodeling in mechanics and pathogenesis of abdominal aortic aneurysms. Acta Biomaterialia, 88, 149–161. (PMID: 10.1016/j.actbio.2019.01.07030735809)
Karlsson, L., Bergqvist, D., Lindbäck, J., & Pärsson, H. (2009). Expansion of small-diameter abdominal aortic aneurysms is not reflected by the release of inflammatory mediators IL-6, MMP-9 and CRP in plasma. European Journal Of Vascular And Endovascular Surgery, 37(4), 420–424. (PMID: 10.1016/j.ejvs.2008.11.02719119028)
Raffort, J., Lareyre, F., Clément, M., Hassen-Khodja, R., Chinetti, G., & Mallat, Z. (2017). Monocytes and macrophages in abdominal aortic aneurysm. Nature Reviews. Cardiology, 14(8), 457–471. (PMID: 10.1038/nrcardio.2017.5228406184)
Marinho, F. V., Brito, C., de Araujo, A., & Oliveira, S. C. (2024). Guanylate-binding protein-5 is involved in inflammasome activation by bacterial DNA but only the cooperation of multiple GBPs accounts for control of Brucella abortus infection. Frontiers In Immunology, 15, 1341464. (PMID: 10.3389/fimmu.2024.13414643840457510885698)
Guo, H., Ni, M., Xu, J., Chen, F., Yao, Z., Yao, Y., Liu, C., & Du, Q. (2021). Transcriptional enhancement of GBP-5 by BATF aggravates sepsis-associated liver injury via NLRP3 inflammasome activation. The FASEB Journal, 35(6), e21672.
Liu, N., Gao, Y., Liu, Y., & Liu, D. (2023). GBP5 Inhibition Ameliorates the Progression of Lupus Nephritis by Suppressing NLRP3 Inflammasome Activation. Immunol Invest, 52(1), 52–66. (PMID: 10.1080/08820139.2022.212283436175170)
Lai, C. H., Wang, K. C., Lee, F. T., Tsai, H. W., Ma, C. Y., Cheng, T. L., Chang, B. I., Yang, Y. J., Shi, G. Y., & Wu, H. L. (2016). Toll-like receptor 4 is essential in the development of abdominal aortic aneurysm. PLoS One, 11(1), e0146565. (PMID: 10.1371/journal.pone.0146565267416944711799)
Huggins, C., Pearce, S., Peri, F., Neumann, F., Cockerill, G., & Pirianov, G. (2015). A novel small molecule TLR4 antagonist (IAXO-102) negatively regulates non-hematopoietic toll like receptor 4 signalling and inhibits aortic aneurysms development. Atherosclerosis, 242(2), 563–570. (PMID: 10.1016/j.atherosclerosis.2015.08.01026318106)
Bian, S., Yang, L., Zhao, D., Lv, L., Wang, T., & Yuan, H. (2023). HMGB1/TLR4 signaling pathway enhances abdominal aortic aneurysm progression in mice by upregulating necroptosis. Inflammation Research, 72(4), 703–713. (PMID: 10.1007/s00011-023-01694-336745209)
Ren, B., Feng, J., Yang, N., Guo, Y., Chen, C., & Qin, Q. (2021). Ginsenoside Rg3 attenuates angiotensin II-induced myocardial hypertrophy through repressing NLRP3 inflammasome and oxidative stress via modulating SIRT1/NF-κB pathway. International Immunopharmacology, 98(107841), 18.
Zhang, J., Yin, Z., Xu, Y., Wei, C., Peng, S., Zhao, M., Liu, J., Xu, S., Pan, W., Zheng, Z., Liu, S., Ye, J., Qin, J. J., Wan, J., & Wang, M. (2023). Resolvin E1/ChemR23 Protects Against Hypertension and Vascular Remodeling in Angiotensin II-Induced Hypertensive Mice. Hypertension, 80(12), 2650–2664. (PMID: 10.1161/HYPERTENSIONAHA.123.2134837800344)
Tsai, S. H., Huang, P. H., Peng, Y. J., Chang, W. C., Tsai, H. Y., Leu, H. B., Chen, J. W., & Lin, S. J. (2013). Zoledronate attenuates angiotensin II-induced abdominal aortic aneurysm through inactivation of Rho/ROCK-dependent JNK and NF-κB pathway. Cardiovasc Res, 100(3), 501–510. (PMID: 10.1093/cvr/cvt23024225494)
Mitchell, J. P., & Carmody, R. J. (2018). NF-κB and the Transcriptional Control of Inflammation. International review of cell and molecular biology, 335, 41–84. https://doi.org/10.1016/bs.ircmb.2017.07.007. (PMID: 10.1016/bs.ircmb.2017.07.00729305014)
Chen, S., Luo, K., Bian, S., Chen, J., Qiu, R., Wu, X., & Li, G. (2021). Paeonol Ameliorates Abdominal Aortic Aneurysm Progression by the NF-κB Pathway. Annals Of Vascular Surgery, 77, 255–262. (PMID: 10.1016/j.avsg.2021.06.00334411666)
Zhai, Z., Zhang, X., Ding, Y., Huang, Z., Li, Q., Zheng, M., Cho, K., Dong, Z., Fu, W., Chen, Z., & Jiang, B. (2022). Eugenol restrains abdominal aortic aneurysm progression with down-regulations on NF-κB and COX-2. Phytotherapy Research: Ptr, 36(2), 928–937. https://doi.org/10.1002/ptr.7358. (PMID: 10.1002/ptr.735835132703)
Zhou, L., Zhao, H., Zhao, H., Meng, X., Zhao, Z., Xie, H., Li, J., Tang, Y., & Zhang, Y. (2023). GBP5 exacerbates rosacea-like skin inflammation by skewing macrophage polarization towards M1 phenotype through the NF-κB signalling pathway. Journal Of The European Academy Of Dermatology And Venereology, 37(4), 796–809. https://doi.org/10.1111/jdv.18725. (PMID: 10.1111/jdv.1872536367676)
Ren, F., Li, J., Ni, X., Yuan, H., & Yan, W. (2024). Knockdown of GBP5 alleviates renal damage caused by psoriasis by regulating NF-κB/STAT3 pathway. Allergologia et immunopathologia, 52(6), 117–127. https://doi.org/10.15586/aei.v52i6.1188. (PMID: 10.15586/aei.v52i6.118839515806)
Qian, G., Adeyanju, O., Olajuyin, A., & Guo, X. (2022). Abdominal aortic aneurysm formation with a focus on vascular smooth muscle cells. Life, 12(2).
Wang, Y., Jia, L., Xie, Y., Cai, Z., Liu, Z., Shen, J., Lu, Y., Su, S., Ma, Y., & Xiang, M. (2019). Involvement of macrophage-derived exosomes in abdominal aortic aneurysms development. Atherosclerosis, 289, 64–72. (PMID: 10.1016/j.atherosclerosis.2019.08.01631479773)
Zhou, Z., Zhou, H., Zou, X., & Wang, X. (2022). RUNX3 is up-regulated in abdominal aortic aneurysm and regulates the function of vascular smooth muscle cells by regulating TGF-β1. Journal Of Molecular Histology, 53(1), 1–11. (PMID: 10.1007/s10735-021-10035-934813022)
Zhang, K., Li, R., Matniyaz, Y., Yu, R., Pan, J., Liu, W., & Wang, D. (2024). Liraglutide attenuates angiotensin II-induced aortic dissection and aortic aneurysm via inhibiting M1 macrophage polarization in APOE (-/-) mice. Biochemical Pharmacology, 223(116170), 26.
Contributed Indexing: Keywords: Abdominal aortic aneurysm; GBP5; M1 macrophage polarization; VSMC phenotypic switching
Substance Nomenclature: 0 (NF-kappa B)
11128-99-7 (Angiotensin II)
EC 3.6.1.- (GTP-Binding Proteins)
0 (Toll-Like Receptor 4)
Entry Date(s): Date Created: 20260416 Date Completed: 20260628 Latest Revision: 20260628
Update Code: 20260628
DOI: 10.1007/s12010-026-05689-8
PMID: 41991765
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1559-0291
DOI:10.1007/s12010-026-05689-8