Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China (S.T., Y.L.); Department of Biochemistry, University of California, Riverside, California (S.T.); Shandong Sport University, Shandong, China (X.G.); Center for Animal Experiment/ABSL-3 Laboratory, Wuhan University, Hubei, China (K.W.); Center for Medical Research, Wuhan University, Hubei, China (K.W.); and Department of Basic Theories, Hubei University of Traditional Chinese Medicine, Hubei, China (H.Y.).
Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China (S.T., Y.L.); Department of Biochemistry, University of California, Riverside, California (S.T.); Shandong Sport University, Shandong, China (X.G.); Center for Animal Experiment/ABSL-3 Laboratory, Wuhan University, Hubei, China (K.W.); Center for Medical Research, Wuhan University, Hubei, China (K.W.); and Department of Basic Theories, Hubei University of Traditional Chinese Medicine, Hubei, China (H.Y.)
J Pharmacol Exp Ther. 2014 Jul;350(1):5-13. doi: 10.1124/jpet.114.212928. Epub 2014 Apr 16.
This study aims to investigate the effects of ramipril (RPL) on endothelial dysfunction associated with diabetes mellitus using cultured human aortic endothelial cells (HAECs) and a type 2 diabetic animal model. The effect of RPL on vasodilatory function in fat-fed, streptozotocin-treated rats was assessed. RPL treatment of 8 weeks alleviated insulin resistance and inhibited the decrease in endothelium-dependent vasodilation in diabetic rats. RPL treatment also reduced serum advanced glycation end products (AGE) concentration and rat aorta reactive oxygen species formation and increased aorta endothelium heme oxygenase-1 (HO-1) expression. Exposure of HAECs to high concentrations of glucose induced prolonged oxidative stress, apoptosis, and accumulation of AGEs. These effects were abolished by incubation of ramiprilat (RPT), the active metabolite of RPL. However, treatment of HAECs with STO-609, a CaMKKβ (Ca(2+)/calmodulin-dependent protein kinase kinase-β) inhibitor; compound C, an AMPK (AMP-activated protein kinase) inhibitor; and Zn(II)PPIX, a selective HO-1 inhibitor, blocked these beneficial effects of RPT. In addition, RPT increased nuclear factor erythroid 2-related factor-2 (Nrf-2) nuclear translocation and activation in a CaMKKβ/AMPK pathway-dependent manner, leading to increased expression of the Nrf-2-regulated antioxidant enzyme, HO-1. The inhibition of CaMKKβ or AMPK by pharmaceutical approach ablated RPT-induced HO-1 expression. Taken together, RPL ameliorates insulin resistance and endothelial dysfunction in diabetes via reducing oxidative stress. These effects are mediated by RPL activation of CaMKK-β, which in turn activates the AMPK-Nrf-2-HO-1 pathway for enhanced endothelial function.
本研究旨在探讨雷米普利（RPL）对培养的人主动脉内皮细胞（HAEC）和 2 型糖尿病动物模型中与糖尿病相关的内皮功能障碍的影响。评估了 RPL 对高脂肪喂养、链脲佐菌素处理的大鼠血管舒张功能的影响。8 周的 RPL 治疗缓解了胰岛素抵抗，并抑制了糖尿病大鼠内皮依赖性血管舒张功能的下降。RPL 治疗还降低了血清晚期糖基化终产物（AGE）浓度和大鼠主动脉活性氧形成，并增加了主动脉内皮血红素加氧酶-1（HO-1）表达。高浓度葡萄糖暴露于 HAEC 可诱导长期氧化应激、细胞凋亡和 AGE 积累。这些作用被 RPL 的活性代谢物雷米普利拉（RPT）孵育所消除。然而，用 STO-609（一种 CaMKKβ（Ca2+/钙调蛋白依赖性蛋白激酶激酶-β）抑制剂）、化合物 C（一种 AMPK（AMP 激活的蛋白激酶）抑制剂）和 Zn(II)PPIX（一种选择性 HO-1 抑制剂）处理 HAEC 可阻断 RPT 的这些有益作用。此外，RPT 以 CaMKKβ/AMPK 通路依赖的方式增加核因子红细胞 2 相关因子 2（Nrf-2）的核易位和激活，导致 Nrf-2 调节的抗氧化酶 HO-1 的表达增加。通过药物方法抑制 CaMKKβ 或 AMPK 可消除 RPT 诱导的 HO-1 表达。总之，RPL 通过减少氧化应激改善糖尿病中的胰岛素抵抗和内皮功能障碍。这些作用是通过 RPL 激活 CaMKK-β 介导的，后者转而激活 AMPK-Nrf-2-HO-1 通路，增强内皮功能。
