A3081 VDR agonist prevents diabetic endothelial dysfunction through inhibition of prolyl isomerase-1 mediated mitochondrial oxidative stress and inflammation

Abstract

Objectives: 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 inhibition of oxidative stress. We aimed to explore the effects of VDR agonist on diabetes-associated endothelial dysfunction and the role of Pin1 in this process. Methods: Streptozocin-induced diabetic mice were treated with vehicle, VDR agonist or Pin1 inhibitor, Juglone 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-kB p65 in high glucose-cultured HUVECs were determined. Results: 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 in vehicle-treated diabetic mice. Additionally, Pin1 protein expression and activity, p66Shc mitochondrial translocation, and NF-kB 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. Conclusion: VDR agonist prevents diabetic endothelial dysfunction through inhibition of Pin1-mediated mitochondrial oxidative stress and inflammation.