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Background and aims <p>Atherosclerosis is a chronic inflammatory disease driven by dysregulated lipid metabolism and macrophage dysfunction. However, the role of <i>Bmp</i> and activin membrane-binding inhibitor (<i>Bambi</i>), a pseudoreceptor that antagonizes <i>Tgfβ </i>superfamily signaling, in modulating these processes remains incompletely characterized.</p> Methods <p>An adenovirus encoding <i>Bambi</i> (Ad-<i>Bambi</i>) was generated and delivered systemically to <i>Apoe</i><sup><i>−/−</i></sup> mice. Atherosclerosis was induced by high-fat diet feeding for 14 weeks, after which plaque development and macrophage phenotypes were assessed.</p> Results <p><i>Bambi</i> 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 (<i>Adgre1</i>) levels by approximately 40% compared to the control group. In vitro, <i>Bamb</i>i overexpression enhanced the lipid metabolic capacity of macrophages, upregulated the cholesterol transporters ATP-binding cassette subfamily A member 1 (<i>Abca1</i>) and ATP-binding cassette subfamily G member 1 (<i>Abcg1</i>), facilitated cholesterol efflux, and suppressed ox-LDL-induced foam cell formation. Transcriptome analysis revealed that <i>Bambi</i> downregulates toll-like receptor 4 (<i>Tlr4</i>) expression via activation of the protein kinase B (<i>Akt</i>) pathway, thereby modulating inflammatory responses and lipid homeostasis in macrophages.</p> Conclusions <p>These findings demonstrate that <i>Bambi</i> alleviates macrophage lipid metabolic dysregulation and inhibits foam cell formation through an <i>Akt</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月24日

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  • Xiaochang Chen,
  • Siyu Tan,
  • Siting Li,
  • Peihong Su,
  • Hua Guan,
  • Aoqi Xiang,
  • Lusha Zhang,
  • Haoping Wang,
  • Qi Yu

摘要

Background and aims

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.

Methods

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.

Results

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.

Conclusions

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.