Aryl hydrocarbon receptor is activated by glucose and regulates the thrombospondin-1 gene promoter in endothelial cells.
Hyperglycemia is an independent risk factor for development of diabetic vascular complications. The molecular mechanisms that are activated by glucose in vascular cells and could explain the development of vascular complications are still poorly understood. A putative binding site for the transcription factor aryl hydrocarbon receptor (AhR) was identified in the glucose-responsive fragment of the promoter of thrombospondin-1, a potent antiangiogenic and proatherogenic protein involved in development of diabetic vascular complications. AhR was expressed in aortic endothelial cells (ECs), activated, and bound to the promoter in response to high glucose stimulation of ECs. The constitutively active form of AhR induced activation of the thrombospondin-1 gene promoter. In response to high glucose stimulation, AhR was found in complex with Egr-1 and activator protein-2, which are 2 other nuclear transcription factors activated by glucose in ECs 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 hexosamine pathway and intracellular glycosylation. This is the first report of activation of AhR (a receptor for xenobiotic compounds) by a physiological stimulus. This report links the activation of AhR to the pathological effects of hyperglycemia in the vasculature.
Department of Molecular Cardiology, Cleveland Clinic, Ohio, USA.
Pankaj
P
Dabir
Tina E
TE
Marinic
Irene
I
Krukovets
Olga I
OI
Stenina
D000818:Animals; D001011:Aorta; D002478:Cells, Cultured / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000209:etiology; D051766:Early Growth Response Protein 1 / Q000502:physiology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006031:Glycosylation; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011499:Protein Processing, Post-Translational; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D019700:Thrombospondin 1 / Q000096:biosynthesis / Q000235:genetics*; D050656:Transcription Factor AP-2 / Q000502:physiology*; D014471:Umbilical Veins
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D018336:Receptors, Aryl Hydrocarbon; D011993:Recombinant Fusion Proteins; D019700:Thrombospondin 1; D050656:Transcription Factor AP-2; D004247:DNA; D005947:Glucose