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Aryl Hydrocarbon Receptor is Activated by High Glucose and Regulates the Thrombospondin‐1 Gene Promoter in Endothelial Cells
Author(s) -
Dabir Pankaj,
Marinic Tina,
Krukovates Irene,
Stenina Olga
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.471.5
Subject(s) - aryl hydrocarbon receptor , chromatin immunoprecipitation , thrombospondin 1 , transcription factor , thrombospondin , receptor , chemistry , promoter , microbiology and biotechnology , biology , biochemistry , gene , gene expression , angiogenesis , cancer research , metalloproteinase , matrix metalloproteinase
Glucose levels correlate directly with the diabetic vascular complications, and the earliest sign of vascular complications is endothelial dysfunction. However, the transcriptional mechanisms activated by glucose in endothelial cells (EC) are poorly understood. Aryl Hydrocarbon Receptor (AhR), a receptor for xenobiotic compounds with unknown physiological function, was activated in EC by high glucose and, as shown by chromatin immunoprecipitation, bound the promoter of thrombospondin‐1, a potent anti‐angiogenic and pro‐atherogenic protein involved in development of diabetic vascular complications. A binding site for AhR was identified in the glucose‐responsive fragment of the promoter (−280/+66), and the deletion of 15 base pairs containing the binding site abrogated the response. The constitutively active rAhR induced activation of the TSP‐1 gene promoter more than 4 fold. In response to high glucose stimulation, AhR formed a complex with Egr‐1 and AP‐2, two other transcription factors activated by glucose in EC that have not been previously detected in complex with AhR. The activity of the DNA‐binding complex was regulated by glucose through the activation of the hexosamine pathway and intracellular glycosylation. This is the first report of activation of AhR by a physiological stimulus. This report links the activation of AhR to the pathological effects of hyperglycemia in the vasculature.