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Background <p>Endothelial to mesenchymal transition (EndMT), the transformation of endothelial cells into a mesenchymal-like state, is regulated by various factors, including transcription factors such as activator protein 1 (AP-1). While recent studies have confirmed the role of EndMT in atherosclerosis, the involvement of AP-1 in EndMT, particularly in the context of human diabetes, remains unclear.</p> Objectives <p>This study aimed to elucidate the role of the AP-1 transcription factor complex in EndMT associated with atherosclerosis in diabetes, utilising both an<i> in vivo</i> preclinical model and an ex vivo model using patient-derived serum for translational relevance. Additionally, it sought to profile gene expression changes following AP-1 inhibition in an EndMT model under high glucose conditions.</p> Methods <p>Serum from patients with and without type 2 diabetes mellitus (T2DM) was used to assess EndMT in primary human aortic endothelial cells (HAECs) in the presence and absence of the AP-1 inhibitor T-5224. EndMT was evaluated through immunofluorescent staining of these cells and of aortic sections from a murine model of diabetes-associated atherosclerosis in a preclinical early intervention study. Furthermore, HAECs were used to explore the effects of AP-1 inhibition on the transcriptional signature of EndMT.</p> Results <p>Patient-derived serum induced EndMT in HAECs, which T-5224 effectively prevented, as confirmed by immunofluorescent staining. Immunofluorescent analysis of the aortic sinus also revealed that T-5224 treatment inhibited EndMT, leading to reduced atherosclerosis in <i>Apoe</i><sup>−/−</sup> mice. In parallel, in the HAECs-based<i> in vitro</i> EndMT model, T-5224 mitigated TNF-α and high glucose-induced EndMT. RNA sequencing identified 242 differentially expressed genes (DEGs) associated with EndMT under high glucose conditions, with T-5224 treatment restoring the expression of 77 DEGs.</p> Conclusion <p>This study identifies AP-1 inhibition with T-5224 as a potential therapeutic approach for EndMT resulting in reduced atherosclerosis in diabetes. The use of human serum underscores the translational relevance of these findings.</p> Graphical abstract

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Activator protein-1 (AP-1) inhibition prevents endothelial to mesenchymal transition in diabetes-associated atherosclerosis: a translational study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月29日

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  • Abdul Waheed Khan,
  • Misbah Aziz,
  • Karly C Sourris,
  • Jairo P Cortes,
  • Tomasz J Block,
  • Aozhi Dai,
  • Scott Maxwell,
  • Jun Okabe,
  • Emma Pyper,
  • Francesco Paneni,
  • Mark E Cooper,
  • Karin AM Jandeleit-Dahm

摘要

Background

Endothelial to mesenchymal transition (EndMT), the transformation of endothelial cells into a mesenchymal-like state, is regulated by various factors, including transcription factors such as activator protein 1 (AP-1). While recent studies have confirmed the role of EndMT in atherosclerosis, the involvement of AP-1 in EndMT, particularly in the context of human diabetes, remains unclear.

Objectives

This study aimed to elucidate the role of the AP-1 transcription factor complex in EndMT associated with atherosclerosis in diabetes, utilising both an in vivo preclinical model and an ex vivo model using patient-derived serum for translational relevance. Additionally, it sought to profile gene expression changes following AP-1 inhibition in an EndMT model under high glucose conditions.

Methods

Serum from patients with and without type 2 diabetes mellitus (T2DM) was used to assess EndMT in primary human aortic endothelial cells (HAECs) in the presence and absence of the AP-1 inhibitor T-5224. EndMT was evaluated through immunofluorescent staining of these cells and of aortic sections from a murine model of diabetes-associated atherosclerosis in a preclinical early intervention study. Furthermore, HAECs were used to explore the effects of AP-1 inhibition on the transcriptional signature of EndMT.

Results

Patient-derived serum induced EndMT in HAECs, which T-5224 effectively prevented, as confirmed by immunofluorescent staining. Immunofluorescent analysis of the aortic sinus also revealed that T-5224 treatment inhibited EndMT, leading to reduced atherosclerosis in Apoe−/− mice. In parallel, in the HAECs-based in vitro EndMT model, T-5224 mitigated TNF-α and high glucose-induced EndMT. RNA sequencing identified 242 differentially expressed genes (DEGs) associated with EndMT under high glucose conditions, with T-5224 treatment restoring the expression of 77 DEGs.

Conclusion

This study identifies AP-1 inhibition with T-5224 as a potential therapeutic approach for EndMT resulting in reduced atherosclerosis in diabetes. The use of human serum underscores the translational relevance of these findings.

Graphical abstract