Role of the aryl hydrocarbon receptor in sugen 5416-induced experimental pulmonary hypertension

Afshan Dean, Teja Gregorc, Craig K. Docherty, Katie Y. Harvey, Margaret Nilsen, Nicholas W. Morrell, Margaret R. MacLean

Research output: Contribution to journalEditorial

5 Citations (Scopus)

Abstract

Rats dosed with the vascular endothelial growth factor inhibitor Sugen 5416 (Su), subjected to hypoxia, and then restored to normoxia have become a widely used model of pulmonary arterial hypertension (PAH). However, the mechanism by which Su exacerbates pulmonary hypertension is unclear. We investigated Su activation of the aryl hydrocarbon receptor (AhR) in human pulmonary artery smooth muscle cells (hPASMCs) and blood outgrowth endothelial cells (BOECs) from female patients with PAH. We also examined the effect of AhR on aromatase and estrogen levels in the lung. Protein and mRNA analyses demonstrated that CYP1A1 was very highly induced in the lungs of Su/hypoxic (Su/Hx) rats. The AhR antagonist CH223191 (8 mg/kg/day) reversed the development of PAH in this model in vivo and normalized lung CYP1A1 expression. Increased lung aromatase and estrogen levels in Su/Hx rats were also normalized by CH223191, as was AhR nuclear translocator (ARNT [HIF-1b]), which is shared by HIF-1a and AhR. Su reduced HIF-1a expression in hPASMCs. Su induced proliferation in BOECs and increased apoptosis in human pulmonary microvascular ECs and also induced translocation of AhR to the nucleus in hPASMCs. Under normoxic conditions, hPASMCs did not proliferate to Su. However, when grown in hypoxia (1%), Su induced hPASMC proliferation. In combination with hypoxia, Su is proliferative in hPASMCs and BOECs from patients with PAH, and Su/Hx-induced PAH in rats may be facilitated by AhR-induced CYP1A1, ARNT, and aromatase. Inhibition of AhR may be a novel approach to the treatment of pulmonary hypertension.

LanguageEnglish
Pages320-330
Number of pages11
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume58
Issue number3
DOIs
Publication statusPublished - 1 Mar 2018

Fingerprint

Aryl Hydrocarbon Receptors
Pulmonary Hypertension
Pulmonary Artery
Smooth Muscle Myocytes
Cytochrome P-450 CYP1A1
Aromatase
Lung
Endothelial Cells
Estrogens
Aryl Hydrocarbon Receptor Nuclear Translocator
Vascular Endothelial Growth Factor A
Cell Proliferation
Apoptosis
Messenger RNA

Keywords

  • aryl hydrocarbon receptor
  • estrogen
  • pulmonary hypertension
  • sugen
  • VEGF

Cite this

Dean, Afshan ; Gregorc, Teja ; Docherty, Craig K. ; Harvey, Katie Y. ; Nilsen, Margaret ; Morrell, Nicholas W. ; MacLean, Margaret R. / Role of the aryl hydrocarbon receptor in sugen 5416-induced experimental pulmonary hypertension. In: American Journal of Respiratory Cell and Molecular Biology. 2018 ; Vol. 58, No. 3. pp. 320-330.
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Role of the aryl hydrocarbon receptor in sugen 5416-induced experimental pulmonary hypertension. / Dean, Afshan; Gregorc, Teja; Docherty, Craig K.; Harvey, Katie Y.; Nilsen, Margaret; Morrell, Nicholas W.; MacLean, Margaret R.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 58, No. 3, 01.03.2018, p. 320-330.

Research output: Contribution to journalEditorial

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T1 - Role of the aryl hydrocarbon receptor in sugen 5416-induced experimental pulmonary hypertension

AU - Dean, Afshan

AU - Gregorc, Teja

AU - Docherty, Craig K.

AU - Harvey, Katie Y.

AU - Nilsen, Margaret

AU - Morrell, Nicholas W.

AU - MacLean, Margaret R.

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AB - Rats dosed with the vascular endothelial growth factor inhibitor Sugen 5416 (Su), subjected to hypoxia, and then restored to normoxia have become a widely used model of pulmonary arterial hypertension (PAH). However, the mechanism by which Su exacerbates pulmonary hypertension is unclear. We investigated Su activation of the aryl hydrocarbon receptor (AhR) in human pulmonary artery smooth muscle cells (hPASMCs) and blood outgrowth endothelial cells (BOECs) from female patients with PAH. We also examined the effect of AhR on aromatase and estrogen levels in the lung. Protein and mRNA analyses demonstrated that CYP1A1 was very highly induced in the lungs of Su/hypoxic (Su/Hx) rats. The AhR antagonist CH223191 (8 mg/kg/day) reversed the development of PAH in this model in vivo and normalized lung CYP1A1 expression. Increased lung aromatase and estrogen levels in Su/Hx rats were also normalized by CH223191, as was AhR nuclear translocator (ARNT [HIF-1b]), which is shared by HIF-1a and AhR. Su reduced HIF-1a expression in hPASMCs. Su induced proliferation in BOECs and increased apoptosis in human pulmonary microvascular ECs and also induced translocation of AhR to the nucleus in hPASMCs. Under normoxic conditions, hPASMCs did not proliferate to Su. However, when grown in hypoxia (1%), Su induced hPASMC proliferation. In combination with hypoxia, Su is proliferative in hPASMCs and BOECs from patients with PAH, and Su/Hx-induced PAH in rats may be facilitated by AhR-induced CYP1A1, ARNT, and aromatase. Inhibition of AhR may be a novel approach to the treatment of pulmonary hypertension.

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KW - estrogen

KW - pulmonary hypertension

KW - sugen

KW - VEGF

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