Aryl Hydrocarbon Receptor Is Activated by Glucose and Regulates the Thrombospondin-1 Gene Promoter in Endothelial Cells

Abstract

Abstract-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.

Highly potent visnagin derivatives inhibit Cyp1 and prevent doxorubicin cardiotoxicity

“…In line with these observations, we noted that zebrafish treated with DOX also demonstrated induction of DHRS13L1, THBS1B, and GSTP2, expression levels that have been previously reported to correlate with AHR activity (16)(17)(18). Thus, we hypothesized that potent analogs of C1 may serve as AHR antagonists.…”

GTP cyclohydrolase I prevents diabetic-impaired endothelial progenitor cells and wound healing by suppressing oxidative stress/thrombospondin-1

“…TSP-1 mRNA and protein levels were significantly increased in the vessel walls of a type 2 diabetic animal model (29). Furthermore, TSP-1 expression increased in response to glucose stimulation in endothelial cells (8). Our study showed that GTPCH I overexpression-induced elevated BH 4 level in EPCs could abolish the increased TSP-1 levels in diabetic mice.…”

Aryl Hydrocarbon Receptor Plays Protective Roles against High Fat Diet (HFD)-induced Hepatic Steatosis and the Subsequent Lipotoxicity via Direct Transcriptional Regulation of Socs3 Gene Expression

“…Indeed, increased adiposity elevates the level of AhR and its target genes (23,24). Although identification of the molecules acts as the ligands or the activator produced under HFD conditions has to be elucidated in future studies, recent studies have identified various low molecular compounds as AhR endogenous ligands or activators, which include glucose, sheared LDL, cAMP derivatives, and tryptophan derivatives (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). These compounds and the related compounds could be contained in HFD or be derived through the metabolic pathway.…”

“…These functional roles of AhR in endobiotic responses are supported by the identification of endogenous ligands or activators (13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

“…Moreover, a comprehensive analysis of gene expression in mice treated with low-dose 2,3,7,8-tetrachlorodibenzo-p-dioxin revealed that hepatic AhR is associated with lipid, glucose, and cholesterol metabolism (25). Finally, identified endogenous ligands or activators, such as arachidonic acid metabolites, modified LDL, and glucose, are known to be involved in energy and lipid metabolism (14,21,22).…”