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) by increasing m ⁶ A methylation in macrophages, which disrupts the stability of CCL5 mRNA. Mechanistically, ALKBH5 promoted senescent foamy macrophage formation through the CCL5/CCR5 (CC chemokine receptor 5)/autophagy signaling pathway. CCL5 also recruited CD8 ⁺ IFN (interferon)γ ⁺ T cells via the CCL5-CCR5 axis. The ALKBH5 inhibitor IOX1 (inhibitor of 2OG oxygenases) and the CCR5 antagonist maraviroc were identified as potential clinical interventions for inhibiting senescent foamy macrophage formation and atherosclerosis progression. CONCLUSIONS: Myeloid ALKBH5 deletion attenuates atherosclerosis progression by suppressing the formation of senescent foamy macrophages and the recruitment of CD8 ⁺ IFNγ ⁺ T cells. These findings identify ALKBH5, CCL5, and CCR5 as novel therapeutic targets for atherosclerosis.

Secretome-based therapies that target angiogenesis are promising for the treatment of ischemic heart disease (IHD). The effects of Chemokine C-C motif ligand (CCL) 28 on IHD remain unclear. In this study, we investigated the role of CCL28 in angiogenesis during IHD in male mice using the myocardial infarction (MI) and hindlimb ischemia (HI) models. The upregulated CCL28/ C-C motif receptor (CCR)10 axis has been observed in HI and MI. Additionally, CCR10 is highly expressed in endothelial cells (ECs). Compared to CCR10^- ECs, CCR10⁺ ECs exhibited robust proangiogenic capacity, which was induced by CCL28 through CCR10/ERK/SOX5 positive feedback signaling. The deletion of CCL28 results in impaired angiogenesis, whereas the use of recombinant CCL28 protein has therapeutic potential for myocardial and hindlimb ischemia, including that in diabetes. Endothelial-specific CCR10 deficiency impairs angiogenesis and blocks the therapeutic effects of rCCL28 in ischemic models. Serum CCL28 levels have a predictive effect on coronary collateral vessels (CCV) in patients with chronic total occlusions. This study highlights the angiogenic role of CCL28 and suggests that recombinant CCL28 protein may be a potential therapeutic option to attenuate IHD.