Ramipril Protects the Endothelium from High Glucose–Induced Dysfunction through CaMKKβ/AMPK and Heme Oxygenase-1 Activation

摘要: This study aims to investigate the effects of ramipril (RPL) on endothelial dysfunction associated with diabetes mellitus using cultured human aortic cells (HAECs) and a type 2 diabetic animal model. The effect RPL vasodilatory function in fat-fed, streptozotocin-treated rats was assessed. treatment 8 weeks alleviated insulin resistance inhibited decrease endothelium-dependent vasodilation rats. also reduced serum advanced glycation end products (AGE) concentration rat aorta reactive oxygen species formation increased endothelium heme oxygenase-1 (HO-1) expression. Exposure HAECs high concentrations glucose induced prolonged oxidative stress, apoptosis, accumulation AGEs. These were abolished by incubation ramiprilat (RPT), active metabolite RPL. However, STO-609, CaMKKβ (Ca(2+)/calmodulin-dependent protein kinase kinase-β) inhibitor; compound C, an AMPK (AMP-activated kinase) Zn(II)PPIX, selective HO-1 inhibitor, blocked these beneficial RPT. In addition, RPT nuclear factor erythroid 2-related factor-2 (Nrf-2) translocation activation CaMKKβ/AMPK pathway-dependent manner, leading expression Nrf-2-regulated antioxidant enzyme, HO-1. inhibition or pharmaceutical approach ablated RPT-induced Taken together, ameliorates via reducing stress. are mediated CaMKK-β, which turn activates AMPK-Nrf-2-HO-1 pathway for enhanced function.