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

Sahoko Ichihara, Ping Li, Nathan Mise, Yuka Suzuki, Kiyora Izuoka, Tamie Nakajima, Frank Gonzalez, Gaku Ichihara

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1543-1553
Number of pages11
JournalArchives of Toxicology
Volume93
Issue number6
DOIs
Publication statusPublished - 1 Jun 2019

Fingerprint

Hypoxia-Inducible Factor 1
Aryl Hydrocarbon Receptors
Ablation
Angiotensin II
Fibrosis
Fenofibrate
Vascular Endothelial Growth Factor A
Endothelins
Heart Ventricles
Aryl Hydrocarbon Receptor Nuclear Translocator
Ligands
Halogenated Hydrocarbons
Aromatic Hydrocarbons
Peroxisome Proliferator-Activated Receptors
Blood Pressure
Blood pressure
Xenobiotics
Polycyclic Aromatic Hydrocarbons
Left Ventricular Hypertrophy
Transcription Factors

Keywords

  • AHR
  • Angiotensin II
  • Cardiac hypertrophy
  • Fibrosis
  • HIF-1α
  • PPARα
  • Vascular endothelial growth factor

Cite this

Ichihara, Sahoko ; Li, Ping ; Mise, Nathan ; Suzuki, Yuka ; Izuoka, Kiyora ; Nakajima, Tamie ; Gonzalez, Frank ; Ichihara, Gaku. / Ablation of aryl hydrocarbon receptor promotes angiotensin II-induced cardiac fibrosis through enhanced c-Jun/HIF-1α signaling. In: Archives of Toxicology. 2019 ; Vol. 93, No. 6. pp. 1543-1553.
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Ablation of aryl hydrocarbon receptor promotes angiotensin II-induced cardiac fibrosis through enhanced c-Jun/HIF-1α signaling. / Ichihara, Sahoko; Li, Ping; Mise, Nathan; Suzuki, Yuka; Izuoka, Kiyora; Nakajima, Tamie; Gonzalez, Frank; Ichihara, Gaku.

In: Archives of Toxicology, Vol. 93, No. 6, 01.06.2019, p. 1543-1553.

Research output: Contribution to journalArticle

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T1 - Ablation of aryl hydrocarbon receptor promotes angiotensin II-induced cardiac fibrosis through enhanced c-Jun/HIF-1α signaling

AU - Ichihara, Sahoko

AU - Li, Ping

AU - Mise, Nathan

AU - Suzuki, Yuka

AU - Izuoka, Kiyora

AU - Nakajima, Tamie

AU - Gonzalez, Frank

AU - Ichihara, Gaku

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AB - 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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