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 language | English |
|---|---|
| Pages (from-to) | 1543-1553 |
| Number of pages | 11 |
| Journal | Archives of Toxicology |
| Volume | 93 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 1 Jun 2019 |
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Keywords
- AHR
- Angiotensin II
- Cardiac hypertrophy
- Fibrosis
- HIF-1α
- PPARα
- Vascular endothelial growth factor
Cite this
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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 journal › Article
TY - JOUR
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
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
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.
KW - AHR
KW - Angiotensin II
KW - Cardiac hypertrophy
KW - Fibrosis
KW - HIF-1α
KW - PPARα
KW - Vascular endothelial growth factor
UR - http://www.scopus.com/inward/record.url?scp=85064814697&partnerID=8YFLogxK
U2 - 10.1007/s00204-019-02446-1
DO - 10.1007/s00204-019-02446-1
M3 - Article
C2 - 31016362
AN - SCOPUS:85064814697
VL - 93
SP - 1543
EP - 1553
JO - Archives of Toxicology
JF - Archives of Toxicology
SN - 0340-5761
IS - 6
ER -