Obesity alters oestrogen metabolism and contributes to pulmonary arterial hypertension

Mair, K. M., Harvey, K. Y., Henry, A. D., Hillyard, D. Z., Nilsen, M. and MacLean, M. R. (2019) Obesity alters oestrogen metabolism and contributes to pulmonary arterial hypertension. European Respiratory Journal, 53(6), 1801524. (doi: 10.1183/13993003.01524-2018) (PMID:30923189) (PMCID:PMC6581204)

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Abstract

Obesity is a common comorbidity for pulmonary arterial hypertension (PAH). Additionally, oestrogen and its metabolites are risk factors for the development of PAH. Visceral adipose tissue (VAT) is a major site of oestrogen production; however, the influence of obesity-induced changes in oestrogen synthesis and metabolism on the development of PAH is unclear. To address this we investigated the effects of inhibiting oestrogen synthesis and metabolism on the development of pulmonary hypertension in male and female obese mice. We depleted endogenous oestrogen in leptin-deficient (ob/ob) mice with the oestrogen inhibitor anastrozole (ANA) and determined the effects on the development of pulmonary hypertension, plasma oestradiol and urinary 16α-hydroxyestrone (16αOHE1). Oestrogen metabolism through cytochrome P450 1B1 (CYP1B1) was inhibited with 2,2′,4,6′-tetramethoxystilbene (TMS). ob/ob mice spontaneously develop pulmonary hypertension, pulmonary vascular remodelling and increased reactive oxygen species production in the lung; these effects were attenuated by ANA. Oestradiol levels were decreased in obese male mice; however, VAT CYP1B1 and 16αOHE1 levels were increased. TMS also attenuated pulmonary hypertension in male ob/ob mice. Intra-thoracic fat from ob/ob mice and VAT conditioned media produce 16αOHE1 and can contribute to oxidative stress, effects that are attenuated by both ANA and TMS. Obesity can induce pulmonary hypertension and changes in oestrogen metabolism, resulting in increased production of 16αOHE1 from VAT that contributes to oxidative stress. Oestrogen inhibitors are now in clinical trials for PAH. This study has translational consequences as it suggests that oestrogen inhibitors may be especially beneficial in treating obese individuals with PAH.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and Harvey, Dr Katie and Nilsen, Mrs Margaret and Mair, Dr Kirsty and Hillyard, Ms Dianne and Henry, Mr Alasdair
Authors: Mair, K. M., Harvey, K. Y., Henry, A. D., Hillyard, D. Z., Nilsen, M., and MacLean, M. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:European Respiratory Journal
Publisher:European Respiratory Society
ISSN:0903-1936
ISSN (Online):1399-3003
Published Online:13 June 2019
Copyright Holders:Copyright © 2019 ERS
First Published:First published in European Respiratory Journal 53(6):1801524
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
722761Sex and the development of pulmonary arterial hypertensionMargaret MacLeanBritish Heart Foundation (BHF)RG/16/2/32153RI CARDIOVASCULAR & MEDICAL SCIENCES