Obesity alters oestrogen metabolism and contributes to pulmonary arterial hypertension.

Autor:	Mair KM; Institute of Cardiovascular and Medical Sciences, College of Medical and Veterinary Science, University of Glasgow, Glasgow, UK.; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK., Harvey KY; Institute of Cardiovascular and Medical Sciences, College of Medical and Veterinary Science, University of Glasgow, Glasgow, UK., Henry AD; Institute of Cardiovascular and Medical Sciences, College of Medical and Veterinary Science, University of Glasgow, Glasgow, UK., Hillyard DZ; Institute of Cardiovascular and Medical Sciences, College of Medical and Veterinary Science, University of Glasgow, Glasgow, UK., Nilsen M; Institute of Cardiovascular and Medical Sciences, College of Medical and Veterinary Science, University of Glasgow, Glasgow, UK.; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK., MacLean MR; Institute of Cardiovascular and Medical Sciences, College of Medical and Veterinary Science, University of Glasgow, Glasgow, UK.; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
Jazyk:	angličtina
Zdroj:	The European respiratory journal [Eur Respir J] 2019 Jun 13; Vol. 53 (6). Date of Electronic Publication: 2019 Jun 13 (Print Publication: 2019).
DOI:	10.1183/13993003.01524-2018
Abstrakt:	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. Competing Interests: Conflict of interest: K.M. Mair has nothing to disclose. Conflict of interest: K.Y. Harvey has nothing to disclose. Conflict of interest: A.D. Henry has nothing to disclose. Conflict of interest: D.Z. Hillyard has nothing to disclose. Conflict of interest: M. Nilsen has nothing to disclose. Conflict of interest: M.R. MacLean has nothing to disclose. (Copyright ©ERS 2019.)
Databáze:	MEDLINE
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