Homoplantaginin alleviates high glucose-induced vascular endothelial barrier dysfunction by regulating Yes-associated...

The vascular endothelial (VE) barrier dysfunction is critical for the onset and progression of diabetic macrovascular complications. Homoplantaginin (HPG), the flavone glucoside hispidulin 7-O-β-d-glucoside, one of the main components of Salvia plebeia R.Br., possesses endothelium protective properties. However, the molecular mechanisms of HPG against diabetic VE barrier dysfunction remain unclear.

To investigate the protective effects and potential mechanisms of HPG on VE barrier function using high glucose (HG)-treated human umbilical vein endothelial cells (HUVECs) and type 1 diabetic (T1D) mice.

In vitro, the protective effect of HPG on endothelial barrier function was assessed by western blotting, RT-qPCR, immunofluorescence, trans endothelial electric resistance, and transwell cell permeability assay. Additionally, T1D mice induced by streptozotocin were gavaged with HPG or combined with EX-527 for 28 days to evaluate the therapeutic effect of HPG.

HPG upregulated the protein and mRNA expression of VE-cadherin, Zonula occludens-1 (ZO-1), occludin, and claudin-1, inhibiting the permeability and the cytoplasmic translocation of high mobility group box 1 (HMGB1) in HG-treated HUVECs. Additionally, HPG significantly inhibited YAP1 phosphorylation, promoted YAP1 nuclear translocation, and enhanced YAP1-SIRT1 interaction. Moreover, molecular docking and cell thermal shift assay revealed that HPG interacted with YAP1. Knockdown of YAP1 gene attenuated the beneficial effect of HPG in vitro. HPG also alleviated glucose and lipid metabolism disorders, oxidative stress, and inflammation; increased the expression of VE-cadherin, ZO-1, SIRT1 and YAP1 in aortic endothelium; improved aortic endothelial barrier function; and attenuated aortic injury in T1D mice. The SIRT1 inhibitor EX-527 significantly reversed the protective effect of HPG on endothelial barrier function in vitro and in vivo.

HPG protects against HG-mediated VE barrier dysfunction via the YAP1/SIRT1/HMGB1 pathway. This study provides valuable insights into HPG as a potential candidate compound for the treatment of diabetic macrovascular complications.