Cardiovascular Research Group, Healthcare Science Research Centre & Manchester Academic Health Science Centre, Faculty of Science and Engineering, Manchester Metropolitan University, UK; Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Egypt.
Cardiovascular Research Group, Healthcare Science Research Centre & Manchester Academic Health Science Centre, Faculty of Science and Engineering, Manchester Metropolitan University, UK.
Biochim Biophys Acta Gen Subj. 2017 Jan;1861(1 Pt A):3311-3322. doi: 10.1016/j.bbagen.2016.08.013. Epub 2016 Aug 21.
Glycomimetics are a diverse array of saccharide-inspired compounds, designed to mimic the bioactive functions of glycosaminoglycans. Therefore, glycomimetics represent a unique source of novel therapies to target aberrant signaling and protein interactions in a wide range of diseases. We investigated the protective effects of four newly synthesized small molecule glycomimetics against lipid-induced endothelial dysfunction, with an emphasis on nitric oxide (NO) and oxidative stress.
Four aromatic sugar mimetics were synthesized by the stepwise transformation of 2,5-dihydroxybenzoic acid to derivatives (C1-C4) incorporating sulfate groups to mimic the structure of heparan sulfate.
Glycomimetic-treated human umbilical vein endothelial cells (HUVECs) were exposed to palmitic acid to model lipid-induced oxidative stress. Palmitate-induced impairment of NO production was restored by the glycomimetics, through activation of Akt/eNOS signaling. Furthermore, C1-C4 significantly inhibited palmitate-induced reactive oxygen species (ROS) production, lipid peroxidation, and activity and expression of NADPH oxidase. These effects were attributed to activation of the Nrf2/ARE pathway and downstream activation of cellular antioxidant and cytoprotective proteins. In ex vivo vascular reactivity studies, the glycomimetics (C1-C4) also demonstrated a significant improvement in endothelium-dependent relaxation and decreased ROS production and NADPH oxidase activity in isolated mouse thoracic aortic rings exposed to palmitate.
The small molecule glycomimetics, C1-C4, protect against lipid-induced endothelial dysfunction through up-regulation of Akt/eNOS and Nrf2/ARE signaling pathways. Thus, carbohydrate-derived therapeutics are a new class of glycomimetic drugs targeting endothelial dysfunction, regarded as the first line of defense against vascular complications in cardiovascular disease.
糖模拟物是一组多种多样的糖启发化合物，旨在模拟糖胺聚糖的生物活性功能。因此，糖模拟物代表了一种独特的新型治疗方法来源，可以针对多种疾病中异常的信号转导和蛋白质相互作用。我们研究了四种新合成的小分子糖模拟物对脂质诱导的内皮功能障碍的保护作用，重点是一氧化氮（NO）和氧化应激。
通过逐步转化 2,5-二羟基苯甲酸来合成四个芳香糖模拟物（C1-C4），其中包含硫酸基团以模拟肝素硫酸盐的结构。
糖模拟物处理的人脐静脉内皮细胞（HUVEC）暴露于棕榈酸以模拟脂质诱导的氧化应激。糖模拟物通过激活 Akt/eNOS 信号转导，恢复了棕榈酸诱导的 NO 产生受损。此外，C1-C4 显著抑制了棕榈酸诱导的活性氧（ROS）产生、脂质过氧化以及 NADPH 氧化酶的活性和表达。这些作用归因于 Nrf2/ARE 通路的激活以及细胞抗氧化和细胞保护蛋白的下游激活。在离体血管反应性研究中，糖模拟物（C1-C4）还显示出在暴露于棕榈酸的分离小鼠胸主动脉环中显著改善内皮依赖性松弛以及减少 ROS 产生和 NADPH 氧化酶活性的作用。
小分子糖模拟物 C1-C4 通过上调 Akt/eNOS 和 Nrf2/ARE 信号通路来保护内皮免受脂质诱导的功能障碍。因此，基于碳水化合物的治疗药物是一种新型的糖模拟药物，针对内皮功能障碍，被认为是心血管疾病中血管并发症的第一道防线。
