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

• Published in: Oxidative medicine and cellular longevity Vol. 2018; no. 2018; pp. 1 - 13
• Main Authors: Peng, Feng, Chai, Dajun, Xu, Chang-Sheng, Lin, Liming, Zhang, Meijin, Lin, Jinxiu
• Format: Journal Article
• Language: English
• Published: Cairo, Egypt Hindawi Publishing Corporation 01.01.2018; Hindawi; John Wiley & Sons, Inc
• Subjects: Agonists; Animals; Apoptosis; Atherosclerosis; Blood coagulation factors; Coronary vessels; Cytokines; Dextrose; Diabetes; Diabetes Mellitus, Experimental - pathology; Disease Models, Animal; Endocrinology; Endothelium; Endothelium, Vascular - pathology; Enzymes; Ethylenediaminetetraacetic acid; Experiments; Glucose; Humans; Inflammation; Inflammation - drug therapy; Inflammation - pathology; Laboratory animals; Male; Metabolism; Metabolites; Mice; Mitochondria - drug effects; Nitric oxide; Oxidative stress; Oxidative Stress - drug effects; Peptidylprolyl Isomerase - antagonists & inhibitors; Phosphorylation; Physiology; Proteins; Receptors, Calcitriol - therapeutic use; Rodents; Transfection; Vitamin D; Vitamin deficiency; China
• DOI: 10.1155/2018/1714896
• ISSN: 1942-0900; 1942-0994

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 μg/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 D3 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-1β, IL-6, and NO in diabetic mice, Pin1 protein expression and activity, subcellular distribution of p66Shc, and NF-κB 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-κB 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.