ADAMTS1 levels were higher in the serum of patients with myocardial fibrosis.
Increased levels of ADAMTS1 and phosphorylated were detected in fibrotic mouse hearts and human cardiac fibroblasts treated with fibrotic factors.
SMAD2 was confirmed to bind to ADAMTS1, indicating a regulatory relationship between the two proteins.
SMAD2 may regulate the expression of ADAMTS1 during fibrosis induced by in cardiac fibroblasts.
Overexpression of ADAMTS1 could enhance collagen production in cardiac fibroblasts stimulated by TGF-β1.
Elevated expression of HDAC6 was observed in CFPMI mouse hearts, and ADAMTS1 may inhibit HDAC6 to influence fibrosis.
Treatment with shRNA-HDAC6 and ADAMTS1 inhibitors in vivo showed potential to reduce myocardial fibrosis and improve cardiac function.
Simplified
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 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 or Ang II were constructed. ChIP was used to confirm that 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.
Key numbers
30
Increased ADAMTS1 Levels
Blood samples from 30 myocardial fibrosis patients were analyzed.
6
Mice per Group
Each experimental group in the mouse model consisted of 6 mice.
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Declarations. Ethics approval and consent to participate: All experiments involving clinical samples were approved by the Ethics Committee of Changsha Central Hospital (2023–151) and carried out according to the Declaration of Helsinki. All experimental procedures were conducted in accordance with institutional guidelines for the use of experimental animals and were approved by the Ethics Committee of the South China University Affiliated Changsha Central Hospital (No. 2022-S0031). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
