Homoplantaginin attenuates high glucose-induced vascular endothelial dysfunction via inhibiting store-operated calcium entry channel and endoplasmic reticulum stress.

Abstract

The activation of store-operated calcium entry (SOCE) channel and endoplasmic reticulum stress (ERS) induced by high glucose (HG) is recognized as a major cause of vascular endothelial dysfunction. This study aims to investigate the protective effect of homoplantaginin (Hom) on HG-induced endothelial dysfunction. HG-induced vascular endothelial dysfunction model in human umbilical vein endothelial cells (HUVECs) and rat-isolated thoracic aortas were established to observe the protective effect of Hom, further evaluated the mechanism of SOCE channel and ERS in the pathogenesis. Hom increased the levels of nitric oxide (NO) and phospho-endothelial nitric oxide synthase (p-eNOS) in HUVECs and isolated rat thoracic aortas in a dose-dependent manner, restored acetylcholine-mediated endothelium-dependent vasodilation. Network pharmacology showed that the pathogenesis of diabetic vascular complications may involve calcium (Ca2+) signal pathway. Hom reduced Ca2+ concentration via blocking SOCE channel in HUVECs, and resisted ERS activation by down-regulating ERS-related proteins expression. Importantly, SKF96365 (SOCE inhibitor) intervention experiment showed that Hom inhibited ERS activation by blocking the SOCE channel, further increased the levels of NO and p-eNOS. Hom could alleviate HG-induced vascular endothelial dysfunction by inhibiting SOCE channel and ERS. This provided a potential pharmacological intervention strategy for the treatment of vascular endothelial dysfunction.