TAT‐beclin1 treatment accelerates the development of atherosclerotic lesions in ApoE‐deficient mice

The importance of autophagy in atherosclerosis has garnered significant attention regarding the potential applications of autophagy inducers. However, the impact of TAT‐Beclin1, a peptide inducer of autophagy, on the development of atherosclerotic plaques remains unclear. Single‐cell omics analysis...

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Bibliographic Details
Published in:The FASEB journal 2024-07, Vol.38 (13), p.e23765-n/a
Main Authors: Liu, Lianbo, Wang, Qingjie, Li, Yawen, Cai, Jiali, Wang, Yexing, Li, Yun, Wang, Ruxing, Sun, Ling, Zheng, Xiaowei, Yin, Anwen
Format: Article
Language:English
Subjects:
atherosclerosis
autophagy
macrophage
Tat‐beclin1
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Summary:The importance of autophagy in atherosclerosis has garnered significant attention regarding the potential applications of autophagy inducers. However, the impact of TAT‐Beclin1, a peptide inducer of autophagy, on the development of atherosclerotic plaques remains unclear. Single‐cell omics analysis indicates a notable reduction in GAPR1 levels within fibroblasts, stromal cells, and macrophages during atherosclerosis. Tat‐beclin1 (T‐B), an autophagy‐inducing peptide derived from Beclin1, could selectively bind to GAPR1, relieving its inhibition on Beclin1 and thereby augmenting autophagosome formation. To investigate its impact on atherosclerosic plaque progression, we established the ApoE−/− mouse model of carotid atherosclerotic plaques. Surprisingly, intravenous administration of Tat‐beclin1 dramatically accelerated the development of carotid artery plaques. Immunofluorescence analysis suggested that macrophage aggregation and autophagosome formation within atherosclerotic plaques were significantly increased upon T‐B treatment. However, immunofluorescence and transmission electron microscopy (TEM) analysis revealed a reduction in autophagy flux through lysosomes. In vitro, the interaction between T‐B and GAPR1 was confirmed in RAW264.7 cells, resulting in the increased accumulation of p62/SQSTM1 and LC3‐II in the presence of ox‐LDL. Additionally, T‐B treatment elevated the protein levels of p62/SQSTM1, LC3‐II, and cleaved caspase 1, along with the secretion of IL‐1β in response to ox‐LDL exposure. In summary, our study underscores that T‐B treatment amplifies abnormal autophagy and inflammation, consequently exacerbating atherosclerotic plaque development in ApoE−/− mice. TAT‐Beclin1 treatment enhances NLRP3 inflammasome‐mediated inflammation and amplifies abnormal autophagy in macrophages, thereby exacerbating atherosclerotic plaque development in ApoE−/− mice.
ISSN:0892-6638
1530-6860
1530-6860
DOI:10.1096/fj.202400161RR