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Ablation of aryl hydrocarbon receptor promotes angiotensin II-induced cardiac fibrosis through enhanced c-Jun/HIF-1α signaling

  • Molecular Toxicology
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Abstract

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 and other xenobiotics. The endogenous ligands and functions of AHR have been the subject of many investigations. In the present study, the potential role of AHR signaling in the development of left ventricular hypertrophy and cardiac fibrosis by angiotensin II (Ang II) infusion was investigated in mice lacking the AHR gene (Ahr−/−). We also assessed the hypothesis that fenofibrate, a peroxisome proliferator-activated receptor-α (PPARα) activator, reduces cardiac fibrosis through the c-Jun signaling. Male Ahr−/− and age-matched wild-type mice (n = 8 per group) were infused with Ang II at 100 ng/kg/min daily for 2 weeks. Treatment with Ang II increased systolic blood pressure to comparable levels in Ahr−/− and wild-type mice. However, Ahr−/− mice developed severe cardiac fibrosis after Ang II infusion compared with wild-type mice. Ang II infusion also significantly increased the expression of endothelin in the left ventricles of Ahr−/− mice, but not in wild-type mice, and significantly increased the c-Jun signaling in Ahr−/− mice. Ang II infusion also significantly enhanced the expression of hypoxia-inducible factor-1α (HIF-1α) and the downstream target vascular endothelial growth factor (VEGF) in the left ventricles of Ahr−/− mice. These results suggested pathogenic roles for the AHR signaling pathway in the development of cardiac fibrosis. Treatment with fenofibrate reduced cardiac fibrosis and abrogated the effects of Ang II on the expression of endothelin, HIF-1α, and VEGF. The inhibitory effect of fenofibrate on cardiac fibrosis was mediated by suppression of VEGF expression through modulation of c-Jun/HIF-1α signaling.

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Acknowledgements

The authors thank Ms Yuka Sakamaki for the secretarial support and Ms Yumiko Tateno for the experimental support. This work was supported in part by a grant from the JSPS KAKENHI Grant Number JP26293149.

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Author notes

  1. Ping Li

    Present address: Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China

  2. Tamie Nakajima

    Present address: Department of Lifelong Sports and Health Sciences, Chubu University, Kasugai, Japan

  3. Gaku Ichihara

    Present address: Department of Occupational and Environmental Health, Tokyo University of Science, Noda, Japan

Authors and Affiliations

  1. Graduate School of Regional Innovation Studies, Mie University, Tsu, Japan

    Sahoko Ichihara, Yuka Suzuki & Kiyora Izuoka

  2. Department of Environmental and Preventive Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, 329-0498, Japan

    Sahoko Ichihara & Nathan Mise

  3. Nagoya University Graduate School of Medicine, Nagoya, Japan

    Ping Li, Tamie Nakajima & Gaku Ichihara

  4. Laboratory of Metabolism, Center of Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD, USA

    Frank Gonzalez

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Ichihara, S., Li, P., Mise, N. et al. Ablation of aryl hydrocarbon receptor promotes angiotensin II-induced cardiac fibrosis through enhanced c-Jun/HIF-1α signaling. Arch Toxicol 93, 1543–1553 (2019). https://doi.org/10.1007/s00204-019-02446-1

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