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

Abstract

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.

Juglone in Oxidative Stress and Cell Signaling

“…Since the identification of the importance of human peptidyl-prolyl cis/trans isomerase Pin1 in Alzheimer’s disease [104] through the modulation of Tau protein [45], Pin1 and juglone have gained considerable attention. As a result, and largely through studies using juglone, Pin1 has also been implicated in a wide variety of clinical conditions including immune response [105], allergy [106], cancer [107,108], hyperparathyroidism [109], rheumatoid arthritis [110], vascular pathology [111,112,113,114,115], diabetes [116], Parkinson’s disease [117], and cardiac fibrosis [118,119,120]. There are numerous review articles already available on Pin1, and thus interested readers should refer to these articles that are found in PubMed and other sources.…”

Correlations among Pulmonary DJ-1, VDR and Nrf-2 in patients with Chronic Obstructive Pulmonary Disease: A Case-control Study

“…VDR was the nuclear receptor for the biologically most active vitamin D metabolite 1α,25-dihydroxyvitamin D3, which not only exerted a significant role in the metabolism and homeostasis of calcium and phosphate, but also involved in the process of cellular proliferation and differentiation, anti-inflammatory and anti-oxidative function [14,[35][36][37][38]. Increasing evidences indicated that VDR played an important function in the process of COPD during the past few decades [39].…”

Anti-Diabetic Atherosclerosis by Inhibiting High Glucose-Induced Vascular Smooth Muscle Cell Proliferation via Pin1/BRD4 Pathway

“…Previous studies have shown that upregulation of Pin1 expression is associated with mitochondrial reactive oxygen species production and mitochondrial damage through interaction with the phosphorylated adaptor protein p66Shc and endothelial nitric oxide synthase. This then leads to endothelial dysfunction and vascular inflammation [ 7 – 9 ]. Additionally, the Pin1 inhibitor juglone is effective in inhibiting diabetic vascular lesions [ 10 ], which is a brown dye isolated from the shell and leaves of the walnut tree [ 11 ].…”