Diabetes accelerates atherosclerosis by driving persistent vascular inflammation. MicroRNA-155 (miR-155) is a post-transcriptional regulator of inflammatory genes, while suppressor of cytokine signali Show more
Diabetes accelerates atherosclerosis by driving persistent vascular inflammation. MicroRNA-155 (miR-155) is a post-transcriptional regulator of inflammatory genes, while suppressor of cytokine signaling 1 (Socs1) limits Janus kinase (JAK)/signal transducer and activator of transcription (STAT)-mediated cytokine responses. We explored how the imbalance between miR-155-5p and Socs1 contributes to atherosclerotic plaque progression in diabetes. Apolipoprotein E knockout (ApoE-/-) mice were studied in two settings: age-dependent atherosclerosis progression under non-diabetic conditions, and streptozotocin-induced diabetes to model accelerated atherosclerosis. Diabetic mice received a miR-155-5p inhibitor, a Socs1-expressing adenovirus, or respective controls. Lesion size, composition, and gene expression were analyzed. Cultured vascular smooth muscle cells (VSMCs) and macrophages were transfected with miR-155-5p mimic/inhibitor and Socs1 siRNA/plasmid to assess inflammatory responses, phenotypes, and efferocytosis under diabetic-like conditions. During atherosclerosis progression, vascular miR-155-5p inversely correlated with Socs1 and positively with lesion size, while Socs1 correlated negatively with plaque burden. In diabetic mice, miR-155-5p inhibition reduced lesion area, lipid/collagen and macrophage/VSMC ratios, pro-inflammatory cytokines, M1 macrophages and synthetic VSMC markers, while increasing Socs1, M2 and contractile VSMC genes. Socs1 gene transfer reproduced these effects by reducing miR-155-5p and Stat1 expression, and lesion size. In vitro, miR-155-5p mimic suppressed Socs1, activated STAT1 and inflammatory phenotypes in macrophages and VSMCs, whereas miR-155-5p inhibition had opposite effects. Socs1 silencing amplified inflammation, and its overexpression counteracted miR-155-5p actions. Moreover, miR-155-5p inhibition reduced soluble Mer receptor tyrosine kinase (MerTK) in plaques and macrophages, indicating improved efferocytosis, whereas the mimic promoted macrophage MerTK shedding and impaired apoptotic cell clearance. Reciprocal regulation between miR-155-5p and Socs1 influences vascular inflammation, phenotypic changes, and defective efferocytosis in a diabetic context. Targeting this axis may restore resolution mechanisms and enhance plaque stability in diabetes-associated vascular disease. The online version contains supplementary material available at 10.1186/s12933-026-03121-3. Show less