Icariin ameliorates endothelial dysfunction in type 1 diabetic rats by suppressing ER stress via the PPARα/Sirt1/AMPKα pathway

Icariin (ICA), as a flavonoid glycoside, is associated with the improvement of vascular complications in diabetes. However, its protective mechanisms remain to be well-established. Here, we tested the hypothesis that ICA attenuates vascular endothelial dysfunction by inhibiting endoplasmic reticulum (ER) stress in type 1 diabetes. In streptozotocin-induced diabetic rats, ICA positively affected acetylcholine-induced vasodilation and phenylephrine-induced vasoconstriction in aortas. ICA treatment significantly attenuated ER stress in diabetic rats and high-glucose induced human umbilical vein endothelial cells. Incubation with ICA in vitro attenuated vascular reactivity in diabetic rats, which was blocked by the ER stress inducer, and Peroxisome Proliferator-activated Receptor α (PPARα), sirtuin1 (SIRT1), or AMP-activated protein kinase-α (AMPKα) inhibitors. Western blot showed that ICA activated the PPARα/SIRT1/AMPKα pathway, which contributed to reducing ER stress and activating endothelial nitric oxide synthase in vivo and vitro. Our results implicate that ICA normalizes ER stress to attenuate endothelial dysfunction by the regulation of the PPARα/SIRT1/AMPKα pathway.