The Natural Protective Mechanism Against Hyperglycemia in Vascular Endothelial Cells

Roles of the Lipid Peroxidation Product 4-Hydroxydodecadienal and Peroxisome Proliferator–Activated Receptor δ

  1. Shlomo Sasson1
  1. 1Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel;
  2. 2Institute of Clinical Biochemistry and Pathobiochemistry, the German Diabetes Center, Düsseldorf, Germany;
  3. 3Université Lille Nord de France, Institut National de la Santé et de la Recherche Médicale (INSERM), U545, UDSL, Institut Pasteur de Lille, Lille, France;
  4. 4Université de Lyon, INSERM UMR870, Insa-Lyon, RMND/IMBL, Inra 1235, Villeurbanne, France.
  1. Corresponding author: Shlomo Sasson, sassolo{at}cc.huji.ac.il.

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-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.

Footnotes

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    • Received August 14, 2009.
    • Accepted January 17, 2010.

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  1. Diabetes vol. 59 no. 4 808-818
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