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The natural protective mechanism against hyperglycemia in vascular endothelial cells: roles of the lipid peroxidation product 4-hydroxydodecadienal and peroxisome proliferator--activated receptor δ
- Source :
- Diabetes. April 1, 2010, Vol. 59 Issue 4, p808, 11 p.
- Publication Year :
- 2010
-
Abstract
- 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 12-1ipoxygenase in this autoregulatory process. The hypothesis that 4-hydroxydodeca-(2E,6Z)-dienal (4-HDDE), the peroxidation product of 12-1ipoxygenase, 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.<br />Hyperglycemia is a major and independent risk factor in the development of cardiovascular disease and atherosclerosis in diabetes (1,2). Vascular endothelial cell (VEC) dysfunction precedes the development of atherosclerotic plaques [...]
- Subjects :
- Vascular endothelium -- Health aspects -- Properties
Carrier proteins -- Health aspects -- Physiological aspects
Biological control systems -- Health aspects
Glucose metabolism -- Health aspects
Hyperglycemia -- Prevention -- Development and progression
Oxidation-reduction reaction -- Health aspects
Health
Subjects
Details
- Language :
- English
- ISSN :
- 00121797
- Volume :
- 59
- Issue :
- 4
- Database :
- Gale General OneFile
- Journal :
- Diabetes
- Publication Type :
- Periodical
- Accession number :
- edsgcl.224990115
- Full Text :
- https://doi.org/10.2337/db09-1207