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Transcriptional regulation of endothelin‐1 by the aryl hydrocarbon receptor

The aryl hydrocarbon receptor (AhR) is an orphan receptor in the basic‐helix‐loop helix‐PAS protein superfamily of transcription factors. Previously, we have shown that AhR null mice exhibit elevated tissue endothelin (ET‐1) mRNA and plasma ET‐1, and develop ET‐1‐dependent hypertension and cardiac hypertrophy. The objective of this study was to determine the degree to which the AhR regulates basal and hypoxia‐dependent induction of ET‐1. First, HUVECs were transfected with AhR siRNA or scrambled control, plus an 854 bp fragment of the murine ET‐1 promoter driving luciferase expression, and were analyzed for AhR mRNA, endogenous preproET‐1 mRNA, and luciferase expression. Second, primary endothelial cells were isolated from AhR wildtype and null mice, treated with control or 120 μM of the hypoxic mimic, desferrioxamine, for 16 hrs, and then analyzed for preproET‐1 mRNA. In HUVECs, AhR siRNA reduced AhR mRNA expression and AhR activity, and significantly increased expression of both endogenous preproET‐1 mRNA and the murine ET‐1 promoter luciferase reporter. In primary murine endothelial cells, genetic deletion of AhR significantly increased basal and hypoxia‐induced preproET‐1 mRNA expression. These data suggest that the AhR acts as a suppressor of basal and hypoxia‐induced preproET‐1 expression and thus may represent a novel therapeutic target for the suppression of ET‐1 transcription and ET‐1‐dependent cardiovascular diseases.