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Downregulation of G3BP2 reduces atherosclerotic lesions in ApoE–/– mice

Lookup NU author(s): Dr Richard Daniel, Dr Ling Juan Wu

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Abstract

© 2020 Elsevier B.V.Background and aims: Atherosclerosis is mainly caused by stress in arterial microenvironments, which results in the formation of stress granules as a consequence of the stress response. As the core protein of stress granules, GTPase-activating protein (SH3 domain)-binding protein 2 (G3BP2) is known to play pivotal roles in tumour initiation, viral infection and Alzheimer's disease, but the role of G3BP2 in atherosclerosis development is poorly understood. Previous studies have shown that vaccination with epitopes from self-antigens could reduce atherosclerotic lesions. Here, we investigated the effect of immunizing ApoE–/– mice with G3BP2 peptides, and whether this immunization exerted an anti-atherogenic effect. Methods and results: In our study, ApoE–/– mice were fed a high-fat diet for 12 weeks from 8 to 20 weeks of age. Then, using a repetitive multiple site strategy, the mice were immunized with a Keyhole limpet haemocyanin (KLH) conjugated G3BP2 peptide for 2 weeks from weeks 16 to 18. High levels of G3BP2 antibodies were detectable before sacrifice. Histological analyses showed that the number of atherosclerotic lesions in ApoE–/– mice was significantly reduced following G3BP2 immunotherapy. The levels of pro-inflammatory cytokines and macrophages were also greatly decreased, while the collagen content of the plaques showed significant increase. Furthermore, knocking down G3BP2 in ApoE–/– mice reduced the number of lesions compared to ApoE–/– mice fed a high-fat diet for eight weeks. In vitro studies demonstrated that G3BP2 regulated ox-LDL-induced inflammation in HUVECs via controlling the localization of IκBα. Conclusions: Immunization with the G3BP2 peptide antigen or knocking down of G3BP2 significantly decreased early atherosclerotic plaques in the ApoE–/– mouse model of atherosclerosis. G3BP2 is a promising potential target for atherosclerosis therapy.


Publication metadata

Author(s): Li T, Safitri M, Zhang K, Wang Y, Huang L, Zhu Y, Daniel R, Wu LJ, Qiu J, Wang G

Publication type: Article

Publication status: Published

Journal: Atherosclerosis

Year: 2020

Volume: 310

Pages: 64-74

Print publication date: 01/10/2020

Online publication date: 26/08/2020

Acceptance date: 20/08/2020

ISSN (print): 0021-9150

ISSN (electronic): 1879-1484

Publisher: Elsevier Ireland Ltd

URL: https://doi.org/10.1016/j.atherosclerosis.2020.08.003

DOI: 10.1016/j.atherosclerosis.2020.08.003

PubMed id: 32919187


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