VDR 激动剂通过抑制脯氨酰异构酶-1 介导的线粒体氧化应激和炎症来预防糖尿病血管内皮功能障碍。
VDR Agonist Prevents Diabetic Endothelial Dysfunction through Inhibition of Prolyl Isomerase-1-Mediated Mitochondrial Oxidative Stress and Inflammation.
机构信息
The First Clinical Medical College, Fujian Medical University, Fuzhou, Fujian, China.
Department of Cardiology, Affiliated Hospital of Putian University, Putian, Fujian, China.
出版信息
Oxid Med Cell Longev. 2018 Apr 15;2018:1714896. doi: 10.1155/2018/1714896. eCollection 2018.
BACKGROUND AND AIM
Upregulation of prolyl isomerase-1 (Pin1) protein expression and activity was associated with the pathogenesis of diabetic vasculopathy through induction of endothelial oxidative stress and inflammation. Moreover, VDR agonist protects against high glucose-induced endothelial apoptosis through the inhibition of oxidative stress. We aimed to explore the effects of the VDR agonist on diabetes-associated endothelial dysfunction and the role of Pin1 in this process.
METHODS
Streptozocin-induced diabetic mice were randomly treated with vehicle, VDR agonist (10 g/kg/d, i.g., twice a week), or Pin1 inhibitor, Juglone (1 mg/kg/d, i.p., every other day), for eight weeks. In parallel, human umbilical vein endothelial cells (HUVECs) exposed to high-glucose condition were treated with 1,25-dihydroxyvitamin D and Juglone or vehicle for 72 hours. Organ chamber experiments were performed to assess endothelium-dependent relaxation to acetylcholine. Circulatory levels of Pin1, SOD, MDA, IL-1, IL-6, and NO in diabetic mice, Pin1 protein expression and activity, subcellular distribution of p66Shc, and NF-B p65 in high glucose-cultured HUVECs were determined.
RESULTS
Both VDR agonist and Juglone significantly improved diabetes-associated endothelial dysfunction and reduced high glucose-induced endothelial apoptosis. Mechanistically, the circulatory levels of SOD and NO were increased compared with those of vehicle-treated diabetic mice. Additionally, Pin1 protein expression and activity, p66Shc mitochondrial translocation, and NF-B p65 in high glucose-cultured HUVECs were also inhibited by VDR agonist and Juglone. Knockdown of VDR abolished the inhibitory effects of VDR agonist on high glucose-induced upregulation of Pin1 protein expression and activity.
CONCLUSIONS
VDR agonist prevents diabetic endothelial dysfunction through inhibition of Pin1-mediated mitochondrial oxidative stress and inflammation.
背景与目的
脯氨酰基异构酶-1（Pin1）蛋白表达和活性的上调与糖尿病血管病变的发病机制有关，通过诱导内皮氧化应激和炎症。此外，维生素 D 受体激动剂通过抑制氧化应激来保护高葡萄糖诱导的内皮细胞凋亡。我们旨在探讨维生素 D 受体激动剂对糖尿病相关内皮功能障碍的影响，以及 Pin1 在这一过程中的作用。
方法
链脲佐菌素诱导的糖尿病小鼠随机接受载体、维生素 D 受体激动剂（10μg/kg/d，ig，每周两次）或 Pin1 抑制剂 Juglone（1mg/kg/d，ip，每隔一天）治疗 8 周。同时，将人脐静脉内皮细胞（HUVECs）暴露于高葡萄糖环境中，用 1,25-二羟基维生素 D 和 Juglone 或载体处理 72 小时。通过器官室实验评估乙酰胆碱依赖性内皮舒张。测定糖尿病小鼠循环中 Pin1、SOD、MDA、IL-1、IL-6 和 NO 的水平，高葡萄糖培养的 HUVECs 中 Pin1 蛋白表达和活性、p66Shc 的亚细胞分布以及 NF-B p65。
结果
维生素 D 受体激动剂和 Juglone 均显著改善了糖尿病相关的内皮功能障碍，并减少了高葡萄糖诱导的内皮细胞凋亡。机制上，与载体处理的糖尿病小鼠相比，循环中的 SOD 和 NO 水平升高。此外，维生素 D 受体激动剂和 Juglone 还抑制了高葡萄糖培养的 HUVECs 中 Pin1 蛋白表达和活性、p66Shc 的线粒体易位以及 NF-B p65。敲低维生素 D 受体消除了维生素 D 受体激动剂对高葡萄糖诱导的 Pin1 蛋白表达和活性上调的抑制作用。
结论
维生素 D 受体激动剂通过抑制 Pin1 介导的线粒体氧化应激和炎症来预防糖尿病内皮功能障碍。
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