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 > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| 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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