The Natural Protective Mechanism Against Hyperglycemia in Vascular Endothelial Cells
| Autor: | Yoav Sin-Malia, Juergen Eckel, Yael Riahi, Guy Cohen, Bart Staels, Evgenia Alpert, Arie Gruzman, Michel Guichardant, Shlomo Sasson |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_specialty
Endocrinology Diabetes and Metabolism Glucose uptake Peroxisome proliferator-activated receptor Polymerase Chain Reaction GW501516 Downregulation and upregulation Internal medicine Internal Medicine medicine Animals Humans PPAR delta RNA Messenger Receptor Aorta chemistry.chemical_classification Aldehydes Glucose Transporter Type 1 biology Glucose transporter medicine.disease Endothelial stem cell Thiazoles Endocrinology Metabolism Glucose chemistry Hyperglycemia biology.protein RNA Original Article Cattle Endothelium Vascular Lipid Peroxidation Rabbits Calreticulin |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | OBJECTIVE Vascular endothelial cells (VECs) downregulate their rate of glucose uptake in response to hyperglycemia by decreasing the expression of their typical glucose transporter GLUT-1. Hitherto, we discovered critical roles for the protein calreticulin and the arachidonic acid–metabolizing enzyme 12-lipoxygenase in this autoregulatory process. The hypothesis that 4-hydroxydodeca-(2E,6Z)-dienal (4-HDDE), the peroxidation product of 12-lipoxygenase, mediates this downregulatory mechanism by activating peroxisome proliferator–activated receptor (PPAR) δ was investigated. RESEARCH DESIGN AND METHODS Effects of 4-HDDE and PPARδ on the glucose transport system and calreticulin expression in primary bovine aortic endothelial cells were evaluated by pharmacological and molecular interventions. RESULTS Using GW501516 (PPARδ agonist) and GSK0660 (PPARδ antagonist), we discovered that high-glucose–induced downregulation of the glucose transport system in VECs is mediated by PPARδ. A PPAR-sensitive luciferase reporter assay in VECs revealed that high glucose markedly increased luciferase activity, while GSK0660 abolished it. High-performance liquid chromatography analysis showed that high-glucose incubation substantially elevated the generation of 4-HDDE in VECs. Treatment of VECs, exposed to normal glucose, with 4-HDDE mimicked high glucose and downregulated the glucose transport system and increased calreticulin expression. Like high glucose, 4-HDDE significantly activated PPARδ in cells overexpressing human PPAR (hPPAR)δ but not hPPARα, -γ1, or -γ2. Moreover, silencing of PPARδ prevented high-glucose–dependent alterations in GLUT-1 and calreticulin expression. Finally, specific binding of PPARδ to a PPAR response element in the promoter region of the calreticulin gene was identified by utilizing a specific chromatin immunoprecipitation assay. CONCLUSIONS Collectively, our data show that 4-HDDE plays a central role in the downregulation of glucose uptake in VECs by activating PPARδ. |
| Databáze: | OpenAIRE |
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