2. Academic Validation
  3. MMP3 as a new target of Danshensu/tetramethylpyrazine derivative for attenuating cardiac fibrosis post-myocardial infarction

MMP3 as a new target of Danshensu/tetramethylpyrazine derivative for attenuating cardiac fibrosis post-myocardial infarction

  • Life Sci. 2025 Jun 1:370:123570. doi: 10.1016/j.lfs.2025.123570.
Wei Huang 1,  Cong He 2,  Hyo In Kim 3,  Xing Gao 4,  Jia You 5,  Tianyue Shao 5,  Yihan Liu 5,  Haodong Wei 5,  Yinan Wang 5,  Jinghao Wang 6,  Yingqi Xu 7,  Junli Guo 8
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou 571199, PR China; Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, School of Public Health, The First Affiliated Hospital, Hainan Medical University, Haikou 571199, PR China.
  • 2 Department of Pharmacology, Harbin Medical University-Daqing, Daqing 163319, PR China.
  • 3 Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston 02215, USA.
  • 4 College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, PR China.
  • 5 Key Laboratory of Tropical Translational Medicine of Ministry of Education, School of Basic Medicine and Life Sciences, Hainan Medical University, Haikou 571199, PR China.
  • 6 Department of Pharmacy, The First Affiliated Hospital, Jinan University, Guangzhou 510630, PR China; The Guangzhou Key Laboratory of Basic and Translational Research on Chronic Diseases, Jinan University, Guangzhou 510630, PR China. Electronic address: wangjinghao@jnu.edu.cn.
  • 7 College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, PR China; College of Pharmacy, Inner Mongolia Medical University, Hohhot 010110, PR China. Electronic address: xuyingqi1987@163.com.
  • 8 Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, School of Public Health, The First Affiliated Hospital, Hainan Medical University, Haikou 571199, PR China. Electronic address: guojl@muhn.edu.cn.
PMID: 40113078 DOI: 10.1016/j.lfs.2025.123570
Abstract

Fibrosis plays a crucial role in the development of cardiac remodeling following acute myocardial infarction (AMI). A novel Danshensu/tetramethylpyrazine derivative (ADTM) has exhibited promising outcomes in the treatment of cardiovascular diseases. However, its impact on cardiac fibrosis remains incompletely understood. In this study, cardiac fibrosis was induced in rats by ligating the left anterior descending coronary artery for 28 days. ADTM demonstrated significant cardioprotective effects. This was evidenced by the alleviation of cardiac dysfunction, a reduction in fibrosis, and the mitigation of endothelial-mesenchymal transition (EndMT) in heart failure rats. In vitro experiments showed that ADTM inhibited cell migration, proliferation, Collagen secretion, and EndMT in both TGF-β1-treated neonatal rat cardiac fibroblasts (CFs) and human coronary artery endothelial cells (HCAECs). Through network pharmacology and molecular docking, matrix metalloproteinase 3 (MMP3) was identified as a potential drug target of ADTM. ADTM suppressed MMP3 upregulation in post-MI hearts and TGF-β1-treated cells, confirming MMP3 as a downstream target of Wnt/β-catenin signaling. Furthermore, the inhibition of MMP3 or β-catenin alleviated the activation of CFs and EndMT in HCAECs in vitro. These findings indicate that ADTM exerts antifibrotic effects by inhibiting MMP3, a potential target of the Wnt/β-catenin pathway. Thus, ADTM represents a novel therapeutic agent for cardiac fibrosis.

Keywords

Cardiac fibrosis; Danshensu/tetramethylpyrazine derivative (ADTM); Endothelial-mesenchymal transition (EndMT); Matrix metalloproteinase 3; Wnt/β-catenin signaling.

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