Abstract 19003: Ablation of Aryl Hydrocarbon Receptor Promotes Angiotensin II-Induced Cardiac Fibrosis by Enhancing c-Jun Transcriptional Activity
Introduction: The aryl hydrocarbon receptor (AHR) is a transcription factor that binds to DNA as a heterodimer with the AHR nuclear translocator (ARNT) after interaction with ligands such as polycyclic and halogenated aromatic hydrocarbons found in tobacco smoke and the environment. We investigated the roles of AHR signaling on the development of left ventricular hypertrophy and cardiac fibrosis by angiotensin II (Ang II) infusion to mice lacking the AHR gene (AHR-/-). Moreover, we tested the hypothesis that peroxisome proliferator-activated receptor-α activator, fenofibrate reduces cardiac fibrosis through the ARNT signaling.
Methods: Male AHR-/- and age-matched wild type (WT) mice (n = 8 for each group) were infused with Ang II at the rate of 100 ng/kg/min for 2 weeks.
Results: Treatment with Ang II elevated systolic blood pressure to comparable levels in AHR-/- and WT mice. AHR-/- mice developed prominent concentric cardiac hypertrophy and prominent fibrosis after Ang II infusion compared with WT mice. The expression of endothelin was significantly enhanced in the left ventricles of AHR-/- mice after Ang II infusion, but not in wild-type mice. Transcriptional activity of c-Jun was significantly increased after Ang II infusion in AHR-/- mice. Moreover, the expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) that is the gene inducible by HIF-1α were also significantly enhanced in the left ventricles of AHR-/- mice after Ang II infusion. Treatment with fenofibrate (100 mg/kg/day for 2 weeks, n = 8) reduced the cardiac fibrosis and suppressed the increases in the expression of endothelin, HIF-1α and VEGF genes.
Conclusions: Ablation of the AHR resulted in enhancement of Ang II-induced cardiac fibrosis. This effect was likely attributable to the associated enhancement of c-Jun transcriptional activity. Treatment with fenofibrate reduced cardiac fibrosis and enhanced VEGF expression through suppression of the c-Jun activity.
Author Disclosures: S. Ichihara: None. Y. Suzuki: None. K. Izuoka: None. G. Ichihara: None.
- © 2016 by American Heart Association, Inc.