Morin, a matrix metalloproteinase 9 inhibitor, attenuates endothelial-to-mesenchymal transition in atherosclerosis by downregulating Notch-1 signaling

  • J Integr Med. 2024 Nov;22(6):683-695. doi: 10.1016/j.joim.2024.11.002.
Yuan He  1 ,  Xiao-Xuan Qin  2 ,  Ming-Wei Liu  1 ,  Wei Sun  3
Affiliations
  • 1. Department of Cardiology, Jiangsu Provincial People's Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
  • 2. Department of Neurology, Jiangsu Provincial People's Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
  • 3. Department of Cardiology, Jiangsu Provincial People's Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. Electronic address: [email protected].
PMID: 39572351 DOI: 10.1016/j.joim.2024.11.002
Abstract

Objective: Atherosclerotic Cardiovascular Disease poses a significant health challenge globally. Recent findings highlight the pivotal role of the endothelial-to-mesenchymal transition (EndMT) in atherosclerosis. Morin is a bioflavonoid mainly extracted from white mulberry, a traditional Chinese herbal medicine with anti-inflammatory and antioxidant properties. This study examines whether morin can alleviate atherosclerosis by suppressing EndMT and seeks to elucidate the underlying mechanism.

Methods: We induced an in vitro EndMT model in human umbilical vein endothelial cells (HUVECs) by stimulating the cells with transforming growth factor-β1 (TGF-β1) (10 ng/mL) for 48 h. The in vivo experiments were performed in an atherosclerosis model using Apolipoprotein E (apoE)-/- mice fed with a high-fat diet (HFD). Mice in the intervention group were given morin (50 mg/kg) orally for 4 weeks. Molecular docking and microscale thermophoresis were assayed to understand the interactions between morin and matrix metalloproteinase-9 (MMP-9).

Results: Morin inhibited the expression of EndMT markers in a dose-dependent manner in TGF-β1-treated HUVECs. Administering 50 μmol/L morin suppressed the upregulation of MMP-9 and Notch-1 signaling in TGF-β1-induced EndMT. Moreover, the overexpression of MMP-9 activated Notch-1 signaling, thereby reversing morin's inhibitory effect on EndMT. In the HFD-induced atherosclerotic apoE-/- mice, morin notably reduced aortic intimal hyperplasia and plaque formation by suppressing EndMT. Furthermore, morin demonstrated a strong binding affinity for MMP-9.

Conclusion: Morin acts as an MMP-9 Inhibitor to disrupt EndMT in atherosclerosis by limiting the activation of Notch-1 signaling. This study underscores morin's potential utility in the development of anti-atherosclerotic medication. Please cite this article as: He Y, Qin XX, Liu MW, Sun W. Morin, a matrix metalloproteinase 9 inhibitor, attenuates endothelial-to-mesenchymal transition in atherosclerosis by downregulating Notch-1 Signaling. J Integr Med. 2024; 22(6): 684-696.

Keywords
Atherosclerosis; Endothelial-to-mesenchymal transition; Matrix metalloproteinase-9; Morin; Traditional Chinese medicine.
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