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

Anne Katrine Z. Johansen, Afshan Dean, Ian Morecroft, Katie Hood, Margaret Nilsen, Lynn Loughlin, Aikaterini Anagnostopoulou, Rhian M. Touyz, Kevin White, Margaret R. MacLean

Research output: Contribution to journalArticle

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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 α 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.

Original languageEnglish
Pages (from-to)82-92
Number of pages11
JournalPulmonary Circulation
Volume6
Issue number1
DOIs
Publication statusPublished - 1 Mar 2016

Fingerprint

Serotonin Plasma Membrane Transport Proteins
Metabolic Networks and Pathways
Pulmonary Hypertension
Cytochrome P-450 Enzyme System
Estrogens
Estrogen Receptor alpha
Serotonin
Monocrotaline
Lung
Smooth Muscle Myocytes
Oxidative Stress
Cell Proliferation
Survival
Antibodies

Keywords

  • cytochrome P450 1B1
  • estrogen
  • hypertension
  • pulmonary
  • serotonin

Cite this

Johansen, A. K. Z., Dean, A., Morecroft, I., Hood, K., Nilsen, M., Loughlin, L., ... MacLean, M. R. (2016). The serotonin transporter promotes a pathological estrogen metabolic pathway in pulmonary hypertension via cytochrome P450 1B1. Pulmonary Circulation, 6(1), 82-92. https://doi.org/10.1086/685023
Johansen, Anne Katrine Z. ; Dean, Afshan ; Morecroft, Ian ; Hood, Katie ; Nilsen, Margaret ; Loughlin, Lynn ; Anagnostopoulou, Aikaterini ; Touyz, Rhian M. ; White, Kevin ; MacLean, Margaret R. / The serotonin transporter promotes a pathological estrogen metabolic pathway in pulmonary hypertension via cytochrome P450 1B1. In: Pulmonary Circulation. 2016 ; Vol. 6, No. 1. pp. 82-92.
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Johansen, AKZ, Dean, A, Morecroft, I, Hood, K, Nilsen, M, Loughlin, L, Anagnostopoulou, A, Touyz, RM, White, K & MacLean, MR 2016, 'The serotonin transporter promotes a pathological estrogen metabolic pathway in pulmonary hypertension via cytochrome P450 1B1', Pulmonary Circulation, vol. 6, no. 1, pp. 82-92. https://doi.org/10.1086/685023

The serotonin transporter promotes a pathological estrogen metabolic pathway in pulmonary hypertension via cytochrome P450 1B1. / Johansen, Anne Katrine Z.; Dean, Afshan; Morecroft, Ian; Hood, Katie; Nilsen, Margaret; Loughlin, Lynn; Anagnostopoulou, Aikaterini; Touyz, Rhian M.; White, Kevin; MacLean, Margaret R.

In: Pulmonary Circulation, Vol. 6, No. 1, 01.03.2016, p. 82-92.

Research output: Contribution to journalArticle

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T1 - The serotonin transporter promotes a pathological estrogen metabolic pathway in pulmonary hypertension via cytochrome P450 1B1

AU - Johansen, Anne Katrine Z.

AU - Dean, Afshan

AU - Morecroft, Ian

AU - Hood, Katie

AU - Nilsen, Margaret

AU - Loughlin, Lynn

AU - Anagnostopoulou, Aikaterini

AU - Touyz, Rhian M.

AU - White, Kevin

AU - MacLean, Margaret R.

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N2 - 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 α 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.

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Johansen AKZ, Dean A, Morecroft I, Hood K, Nilsen M, Loughlin L et al. The serotonin transporter promotes a pathological estrogen metabolic pathway in pulmonary hypertension via cytochrome P450 1B1. Pulmonary Circulation. 2016 Mar 1;6(1):82-92. https://doi.org/10.1086/685023