Bambi/Akt/Tlr4 axis protects against atherosclerosis by maintaining lipid metabolism homeostasis in macrophages

Atherosclerosis is a chronic inflammatory disease driven by dysregulated lipid metabolism and macrophage dysfunction. However, the role of Bmp and activin membrane-binding inhibitor (Bambi), a pseudoreceptor that antagonizes Tgfβ superfamily signaling, in modulating these processes remains incompletely characterized. An adenovirus encoding Bambi (Ad-Bambi) was generated and delivered systemically to Apoe−/− mice. Atherosclerosis was induced by high-fat diet feeding for 14 weeks, after which plaque development and macrophage phenotypes were assessed. Bambi overexpression significantly attenuated the aortic atherosclerotic plaques area, promoted a shift in macrophage polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype, and significantly reduced the secretion of key inflammatory cytokines, most notably reducing adhesion G protein-coupled receptor E1 (Adgre1) levels by approximately 40% compared to the control group. In vitro, Bambi overexpression enhanced the lipid metabolic capacity of macrophages, upregulated the cholesterol transporters ATP-binding cassette subfamily A member 1 (Abca1) and ATP-binding cassette subfamily G member 1 (Abcg1), facilitated cholesterol efflux, and suppressed ox-LDL-induced foam cell formation. Transcriptome analysis revealed that Bambi downregulates toll-like receptor 4 (Tlr4) expression via activation of the protein kinase B (Akt) pathway, thereby modulating inflammatory responses and lipid homeostasis in macrophages. These findings demonstrate that Bambi alleviates macrophage lipid metabolic dysregulation and inhibits foam cell formation through an Akt-dependent signaling mechanism. This suggests that Bambi may exert atheroprotective effect during disease and represents a potential therapeutic target for the prevention or treatment of atherosclerosis.