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

Abstract EN

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.