Dexfenfluramine and the oestrogen-metabolizing enzyme CYP1B1 in the development of pulmonary arterial hypertension

Dempsie, Y., MacRitchie, N.A., White, K., Morecroft, I., Wright, A.F., Nilsen, M., Loughlin, L., Mair, K.M. and MacLean, M.R. (2013) Dexfenfluramine and the oestrogen-metabolizing enzyme CYP1B1 in the development of pulmonary arterial hypertension. Cardiovascular Research, 99(1), pp. 24-34. (doi:10.1093/cvr/cvt064) (PMID:23519266) (PMCID:PMC3687748)

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Abstract

<p>Aims: Pulmonary arterial hypertension (PAH) occurs more frequently in women than men. Oestrogen and the oestrogen-metabolising enzyme cytochrome P450 1B1 (CYP1B1) play a role in the development of PAH. Anorectic drugs such as dexfenfluramine (Dfen) have been associated with the development of PAH. Dfen mediates PAH via a serotonergic mechanism and we have shown serotonin to up-regulate expression of CYP1B1 in human pulmonary artery smooth muscle cells (PASMCs). Thus here we assess the role of CYP1B1 in the development of Dfen-induced PAH.</p> <p>Methods and results: Dfen (5 mg kg−1 day−1 PO for 28 days) increased right ventricular pressure and pulmonary vascular remodelling in female mice only. Mice dosed with Dfen showed increased whole lung expression of CYP1B1 and Dfen-induced PAH was ablated in CYP1B1−/− mice. In line with this, Dfen up-regulated expression of CYP1B1 in PASMCs from PAH patients (PAH-PASMCs) and Dfen-mediated proliferation of PAH-PASMCs was ablated by pharmacological inhibition of CYP1B1. Dfen increased expression of tryptophan hydroxylase 1 (Tph1; the rate-limiting enzyme in the synthesis of serotonin) in PAH-PASMCs and both Dfen-induced proliferation and Dfen-induced up-regulation of CYP1B1 were ablated by inhibition of Tph1. 17β-Oestradiol increased expression of both Tph1 and CYP1B1 in PAH-PASMCs, and Dfen and 17β-oestradiol had synergistic effects on proliferation of PAH-PASMCs. Finally, ovariectomy protected against Dfen-induced PAH in female mice.</p> <p>Conclusion: CYP1B1 is critical in the development of Dfen-induced PAH in mice in vivo and proliferation of PAH-PASMCs in vitro. CYP1B1 may provide a novel therapeutic target for PAH.</p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and Morecroft, Dr Ian and Dempsie, Dr Yvonne and Loughlin, Mrs Lynn and Nilsen, Mrs Margaret and Mair, Dr Kirsty and White, Dr Kevin and MacRitchie, Dr Neil
Authors: Dempsie, Y., MacRitchie, N.A., White, K., Morecroft, I., Wright, A.F., Nilsen, M., Loughlin, L., Mair, K.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
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Cardiovascular Research
Journal Abbr.:Cardiovasc Res
Publisher:Oxford University Press
ISSN:0008-6363
ISSN (Online):1755-3245
Published Online:20 March 2013
Copyright Holders:Copyright © 2013 The Authors
First Published:First published in Cardiovascular Research
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
490991Effect of oestrogen on the serotonin system: role in the development of pulmonary hypertensionMargaret MacleanMedical Research Council (MRC)G0801171RI CARDIOVASCULAR & MEDICAL SCIENCES
573731Gender and the development of pulmonary arterial hypertension: regulation of genes from mouse to manMargaret MacleanBritish Heart Foundation (BHF)RG/11/7/28916RI CARDIOVASCULAR & MEDICAL SCIENCES
418441Capacity Building Award in Integrative Mammalian BiologyMargaret MacleanBiotechnology and Biological Sciences Research Council (BBSRC)BB/E527071/1RI CARDIOVASCULAR & MEDICAL SCIENCES