VDR Agonist Prevents Diabetic Endothelial Dysfunction through Inhibition of Prolyl Isomerase-1-Mediated Mitochondrial Oxidative Stress and Inflammation

作者：Zhang, Meijin; Lin, Liming; Xu, Changsheng; Chai, Dajun^*; Peng, Feng^*; Lin, Jinxiu^*

来源：Oxidative Medicine and Cellular Longevity, 2018, 2018: 1714896.

DOI：10.1155/2018/1714896

• NITRIC-OXIDE SYNTHASE
• VITAMIN-D
• REACTIVE OXYGEN
• ISOMERASE PIN1
• MOLECULAR SWITCH
• NADPH OXIDASE
• KAPPA-B
• CELLS
• ACTIVATION
• DISEASE

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 mu 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-3 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 beta, IL-6, and NO in diabetic mice, Pin1 protein expression and activity, subcellular distribution of p66Shc, and NF-kappa 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-kappa 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.

• 出版日期2018
• 单位莆田学院; 福建医科大学