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VDR Agonist Prevents Diabetic Endothelial Dysfunction through Inhibition of Prolyl Isomerase-1-Mediated Mitochondrial Oxidative Stress and Inflammation
- Source :
- Oxidative Medicine and Cellular Longevity, Vol 2018 (2018), Oxidative Medicine and Cellular Longevity
- Publication Year :
- 2018
- Publisher :
- Hindawi, 2018.
-
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.
- Subjects :
- Male
0301 basic medicine
Agonist
Aging
medicine.medical_specialty
Endothelium
Article Subject
medicine.drug_class
030204 cardiovascular system & hematology
Transfection
medicine.disease_cause
Biochemistry
Calcitriol receptor
Diabetes Mellitus, Experimental
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Downregulation and upregulation
Internal medicine
medicine
Animals
Humans
Endothelial dysfunction
lcsh:QH573-671
Receptor
Inflammation
lcsh:Cytology
Cell Biology
General Medicine
Peptidylprolyl Isomerase
medicine.disease
Mitochondria
Disease Models, Animal
Oxidative Stress
030104 developmental biology
Endocrinology
medicine.anatomical_structure
chemistry
Receptors, Calcitriol
Endothelium, Vascular
Juglone
Oxidative stress
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 19420900
- Database :
- OpenAIRE
- Journal :
- Oxidative Medicine and Cellular Longevity
- Accession number :
- edsair.doi.dedup.....52dcff93cc97e7b99fb311bf34479939
- Full Text :
- https://doi.org/10.1155/2018/1714896