Role of the Aryl Hydrocarbon Receptor in Sugen 5416–induced Experimental Pulmonary Hypertension

Autor: Teja Gregorc, Craig K. Docherty, Afshan Dean, Margaret R. MacLean, Katie Y. Harvey, Margaret Nilsen, Nicholas W. Morrell
Rok vydání: 2018
Předmět:
Vascular Endothelial Growth Factor A
0301 basic medicine
Indoles
Clinical Biochemistry
Apoptosis
Muscle
Smooth
Vascular
0302 clinical medicine
Aromatase
Lung
Original Research
biology
respiratory system
Cell Hypoxia
medicine.anatomical_structure
Female
medicine.symptom
Pulmonary and Respiratory Medicine
medicine.medical_specialty
Aryl hydrocarbon receptor nuclear translocator
medicine.drug_class
Hypertension
Pulmonary
Active Transport
Cell Nucleus
03 medical and health sciences
Internal medicine
Cytochrome P-450 CYP1A1
medicine
Animals
Humans
Pyrroles
RNA
Messenger
Rats
Wistar
Molecular Biology
Cell Proliferation
Aryl Hydrocarbon Receptor Nuclear Translocator
Endothelial Cells
Estrogens
Cell Biology
Hypoxia (medical)
Hypoxia-Inducible Factor 1
alpha Subunit
Aryl hydrocarbon receptor
medicine.disease
Pulmonary hypertension
Rats
respiratory tract diseases
030104 developmental biology
Endocrinology
Receptors
Aryl Hydrocarbon
030228 respiratory system
Estrogen
biology.protein
Pyrazoles
Azo Compounds
Zdroj: American Journal of Respiratory Cell and Molecular Biology. 58:320-330
ISSN: 1535-4989
1044-1549
DOI: 10.1165/rcmb.2017-0260oc
Popis: Rationale: Rats dosed with the vascular endothelial growth factor (VEGF) inhibitor Sugen 5416 (Su), placed in hypoxia then restored to normoxia has become a widely used model of pulmonary arterial hypertension (PAH). The mechanism by which Su exaccerbates pulmonary hypertension is, however, unclear. Objectives: We investigated Su-activation of the aryl hydrocarbon receptor (AhR) in patient human pulmonary arterial smooth muscle cells (hPASMCs) and patient blood outgrowth endothelial cells (BOECs). We also examined the effect of AhR on aromatase and estrogen levels in the lung. Methods, Measurements and Main Results: Protein and mRNA analysis demonstrated that CYP1A1 was very highly induced in the lungs of Su/hypoxic (Su/Hx) rats. The AhR antagonist CH223191 (8mg/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-1β]) which is shared by HIF-1α and AhR. Su reduced HIF1α expression in hPASMCs. Su induced proliferation in BOECs and increased apoptosis in human pulmonary microvascular endothelial cells (hPMECs) and also induced translocation of AhR to the nucleus in hPASMCs. Under normoxic conditions, hPASMCs do not proliferate to Su. However when grown in hypoxia (1%) Su induced hPASMC proliferation. Conclusion: In combination with hypoxia, Su is proliferative in patient hPASMCs and patient BOECs and Su/Hx-induced PAH in rats may be facilitated by AhR-induced CYP1A1, ARNT and aromatase. Inhibition of the AhR receptor may be a novel approach to the treatment of pulmonary hypertension.
Databáze: OpenAIRE
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