ALKBH5 Regulates Macrophage Senescence and Accelerates Atherosclerosis by Promoting CCL5 m 6 A Modification

作者：Rifeng Gao, Jiaran Shi, Yang Lyu, Bichen Ren, Wei Wei, Jiahui Cheng, Juntao Chen, Yan Zhou, Jianxin Chen, Xiaolei Sun, Jun Jiang, Bo Li, Kun Yang · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2025 · DOI：10.1161/atvbaha.125.322508 · 被引用次数：18 · 研究领域：Immune cells in cancer、interferon and immune responses、Cytokine Signaling Pathways and Interactions

BACKGROUND: Senescent foamy macrophages are key drivers of atherosclerosis and plaque instability. N 6 -methyladenosine (m 6 A) modification of RNA plays an important role in the development of various diseases including aging. Here, we aim to investigate the role of m 6 A modification of RNA in the formation of senescent foamy macrophages in atherosclerosis. METHODS: To assess m 6 A methylation, macrophages were isolated from the atherosclerotic plaques of patients with atherosclerosis, and Apoe −/− mice were fed a high-fat diet using flow cytometry. An ALKBH5 (alkB homolog 5) f/f , Lyz2 (lysozyme 2) Cre , Apoe −/− mouse model was generated to determine the infiltration of senescent foamy macrophages into plaques and atherosclerosis progression. Methylated RNA immunoprecipitation, RNA immunoprecipitation sequencing, and dual-luciferase assays were performed to explore the mechanisms underlying the ALKBH5-mediated formation of senescent foamy macrophages. RESULTS: Decreased m 6 A methylation and increased ALKBH5 expression were observed in arterial plaques and infiltrating macrophages from patients and mice with atherosclerosis. Compared with control mice, ALKBH5 f/f , Lyz2 Cre , Apoe −/− mice exhibited fewer atherosclerosis plaques with greater stability, which was attributed to the suppression of senescent foamy macrophage formation and senescence-associated secretory phenotype. In addition, ALKBH5 deletion reduced the mRNA expression level of CCL5 (CC chemokine ligand 5) b...