Pinoresinol Diglucoside Alleviates Cardiac Fibrosis Through Inhibiting Endothelial–Mesenchymal Transition via the Transforming Growth Factor‐ <scp>β1</scp> /Smads Pathway in <scp>db/db</scp> Mice

This study aimed to investigate the protective effect of pinoresinol diglucoside (PDG) on diabetic cardiomyopathy (DCM)-induced cardiac fibrosis. In vivo, we used leptin receptor-deficient (db/db) mice and db/m mice as the mouse model of DCM. In vitro, H9c2 cells and human umbilical vein endothelial cells (HUVECs) were exposed to high glucose to establish the model of DCM and endothelial-mesenchymal transition (EndMT). Using qRT-PCR, confocal microscopy, and western blot, the changes in diabetic cardiac fibrosis, EndMT, and the expression of the TGF-β1/Smads signaling pathway were evaluated, respectively. A significant increase in blood glucose, more serious fibrosis of the interstitial and perivascular areas, and higher mRNA levels of fibrotic markers (Col1a1, Col3a1, and Postn) were observed in db/db mice rather than the control mice. Intriguingly, EndMT was triggered in db/db mice, exhibiting a decrease in the endothelial markers (CD31, Cdh5, and Cldn5) and an increase in the mesenchymal markers (α-SMA and FN1) at the mRNA level. However, PDG or Rosi treatment could reverse these changes. Concurrently, PDG inhibited the fibrotic response and the process of EndMT induced by HG in H9c2 cells and HUVECs. Mechanistically, PDG downregulated the expression of the TGF-β1/Smads signaling pathway under the condition of DCM. Notably, the effect of PDG on EndMT was abolished by siTGF-β1 in HUVECs. Therefore, PDG effectively alleviated T2DM-caused myocardial fibrosis, which might be through the downregulation of the TGF-β1/Smads pathway. This study provides a new insight for PDG on the prevention and treatment of DCM.