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Background <p>A disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) is involved in the occurrence and development of myocardial fibrosis. Here, we sought to explore the specific regulatory mechanism of ADAMTS1 in cardiac fibrosis post-myocardial infarction (CFPMI).</p> Methods <p>Blood samples from patients with myocardial fibrosis were collected. A CFPMI mouse model and in vitro models involving human or mouse cardiac fibroblasts treated with TGF-β1 or Ang II were constructed. ChIP was used to confirm that SMAD2 binds to ADAMTS1, and Co-IP was used to verify the interaction between ADAMTS1 and HDAC6. Cellular models with SMAD2 knockdown, ADAMTS1 regulation, and HDAC6 inhibitor treatment were used to study their roles in fibrosis. Finally, AAV-shRNA-HDAC6 and ADAMTS1 inhibitor effects were verified in vivo.</p> Results <p>ADAMTS1 levels were higher in myocardial fibrosis patients’ serum. Increased ADAMTS1 and p-SMAD2 were found in fibrotic mouse hearts and human cardiac fibroblasts stimulated with fibrotic factors. ChIP validated the binding of SMAD2 to ADAMTS1. Mechanistically, SMAD2 regulated ADAMTS1 expression during TGF-β1-induced fibrosis in human and mouse cardiac fibroblasts. Overexpression of ADAMTS1 enhanced the production of collagen fiber proteins in human and mouse cardiac fibroblasts induced by TGF-β1. Moreover, HDAC6 expression was elevated in CFPMI mouse hearts and ADAMTS1 inhibited HDAC6 to regulate fibrosis. ADAMTS1 interacted with HDAC6 during fibrosis. In vivo, shRNA-HDAC6 and ADAMTS1 inhibitor treatment alleviated myocardial fibrosis and improved cardiac function after CFPMI.</p> Conclusions <p>Targeting ADAMTS1/HDAC6 alleviated TGF-β1/SMAD2-associated cardiac fibrosis in CFPMI. This study may provide a novel theoretical basis for the treatment of myocardial fibrosis.</p>

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Targeting ADAMTS1/HDAC6 alleviates TGF-β1/SMAD2-associated cardiac fibrosis in cardiac fibrosis post-myocardial infarction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月12日

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  • Qiao Jin,
  • Chun Chen,
  • Pengcui Wu,
  • Liang Li,
  • Luping Jiang,
  • Ran Chen,
  • Shanxiang Xu,
  • Yuyan Huang,
  • Haixia Xu,
  • Xiao Long

摘要

Background

A disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) is involved in the occurrence and development of myocardial fibrosis. Here, we sought to explore the specific regulatory mechanism of ADAMTS1 in cardiac fibrosis post-myocardial infarction (CFPMI).

Methods

Blood samples from patients with myocardial fibrosis were collected. A CFPMI mouse model and in vitro models involving human or mouse cardiac fibroblasts treated with TGF-β1 or Ang II were constructed. ChIP was used to confirm that SMAD2 binds to ADAMTS1, and Co-IP was used to verify the interaction between ADAMTS1 and HDAC6. Cellular models with SMAD2 knockdown, ADAMTS1 regulation, and HDAC6 inhibitor treatment were used to study their roles in fibrosis. Finally, AAV-shRNA-HDAC6 and ADAMTS1 inhibitor effects were verified in vivo.

Results

ADAMTS1 levels were higher in myocardial fibrosis patients’ serum. Increased ADAMTS1 and p-SMAD2 were found in fibrotic mouse hearts and human cardiac fibroblasts stimulated with fibrotic factors. ChIP validated the binding of SMAD2 to ADAMTS1. Mechanistically, SMAD2 regulated ADAMTS1 expression during TGF-β1-induced fibrosis in human and mouse cardiac fibroblasts. Overexpression of ADAMTS1 enhanced the production of collagen fiber proteins in human and mouse cardiac fibroblasts induced by TGF-β1. Moreover, HDAC6 expression was elevated in CFPMI mouse hearts and ADAMTS1 inhibited HDAC6 to regulate fibrosis. ADAMTS1 interacted with HDAC6 during fibrosis. In vivo, shRNA-HDAC6 and ADAMTS1 inhibitor treatment alleviated myocardial fibrosis and improved cardiac function after CFPMI.

Conclusions

Targeting ADAMTS1/HDAC6 alleviated TGF-β1/SMAD2-associated cardiac fibrosis in CFPMI. This study may provide a novel theoretical basis for the treatment of myocardial fibrosis.