The serotonin transporter promotes a pathological estrogen metabolic pathway in pulmonary hypertension via cytochrome P450 1B1 pulmonary circulation

Johansen, A. K. Z., Dean, A., Morecroft, I., Hood, K., Nilsen, M., Loughlin, L., Anagnostopoulou, A., Touyz, R. M. , White, K. and MacLean, M. R. (2016) The serotonin transporter promotes a pathological estrogen metabolic pathway in pulmonary hypertension via cytochrome P450 1B1 pulmonary circulation. Pulmonary Circulation, 6(1), pp. 82-92. (doi:10.1086/685023) (PMID:27162617) (PMCID:PMC4860551)

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Abstract

Pulmonary arterial hypertension (PAH) is a devastating vasculopathy that predominates in women and has been associated with dysregulated estrogen and serotonin signaling. Overexpression of the serotonin transporter (SERT+) in mice results in an estrogen-dependent development of pulmonary hypertension (PH). Estrogen metabolism by cytochrome P450 1B1 (CYP1B1) contributes to the pathogenesis of PAH, and serotonin can increase CYP1B1 expression in human pulmonary arterial smooth muscle cells (hPASMCs). We hypothesized that an increase in intracellular serotonin via increased SERT expression may dysregulate estrogen metabolism via CYP1B1 to facilitate PAH. Consistent with this hypothesis, we found elevated lung CYP1B1 protein expression in female SERT+ mice accompanied by PH, which was attenuated by the CYP1B1 inhibitor 2,3',4,5'-tetramethoxystilbene (TMS). Lungs from female SERT+ mice demonstrated an increase in oxidative stress that was marked by the expression of 8-hydroxyguanosine; however, this was unaffected by CYP1B1 inhibition. SERT expression was increased in monocrotaline-induced PH in female rats; however, TMS did not reverse PH in monocrotaline-treated rats but prolonged survival. Stimulation of hPASMCs with the CYP1B1 metabolite 16α-hydroxyestrone increased cellular proliferation, which was attenuated by an inhibitor (MPP) of estrogen receptor alpha (ERα) and a specific ERα antibody. Thus, increased intracellular serotonin caused by increased SERT expression may contribute to PAH pathobiology by dysregulation of estrogen metabolic pathways via increased CYP1B1 activity. This promotes PASMC proliferation by the formation of pathogenic metabolites of estrogen that mediate their effects via ERα. Our studies indicate that targeting this pathway in PAH may provide a promising antiproliferative therapeutic strategy.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and Dean, Dr Afshan and Anagnostopoulou, Dr Aikaterini and White, Dr Kevin and Loughlin, Mrs Lynn and Nilsen, Mrs Margaret and Touyz, Professor Rhian and Johansen, Miss Anne Katrine and Morecroft, Dr Ian
Authors: Johansen, A. K. Z., Dean, A., Morecroft, I., Hood, K., Nilsen, M., Loughlin, L., Anagnostopoulou, A., Touyz, R. M., White, K., and MacLean, M. R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Pulmonary Circulation
Publisher:Medknow Publications
ISSN:2045-8932
ISSN (Online):2045-8940
Published Online:05 February 2016

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
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
573733Gender 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