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

Dean, A., Gregorc, T., Docherty, C. K., Harvey, K. Y., Nilsen, M., Morrell, N. W. and MacLean, M. R. (2018) Role of the aryl hydrocarbon receptor in Sugen 5416-induced experimental pulmonary hypertension. American Journal of Respiratory Cell and Molecular Biology, 58(3), pp. 320-330. (doi:10.1165/rcmb.2017-0260OC) (PMID:28956952)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Mandy and Gregorc, Teja and Dean, Dr Afshan and Harvey, Dr Katie and Docherty, Dr Craig and Nilsen, Mrs Margaret
Authors: Dean, A., Gregorc, T., Docherty, C. K., Harvey, K. Y., Nilsen, M., Morrell, N. W., and MacLean, M. R.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:American Journal of Respiratory Cell and Molecular Biology
Publisher:American Thoracic Society
ISSN:1044-1549
ISSN (Online):1535-4989
Published Online:28 September 2017
Copyright Holders:Copyright © 2017 American Thoracic Society
First Published:First published in American Journal of Respiratory Cell and Molecular Biology 58(3): 320-330
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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