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

Abstract

AimsPulmonary 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.Methods and resultsDfen (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.ConclusionCYP1B1 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.

Sex-Dependent Influence of Endogenous Estrogen in Pulmonary Hypertension

“…Increased synthesis of estrogen has been clinically associated with portopulmonary hypertension (15) and estrogen is causative in female susceptible models of PH (7)(8)(9). Studies into the role of estrogen in PAH have failed to reach a consensus, mainly because of the variety of experimental approaches adopted.…”

“…Recently, we have described novel murine models where only female animals develop PH, such as mice overexpressing the serotonin transporter gene (SERT1 mouse) (7) and Mts1 (8). In these models the predominant circulating estrogen 17b-estradiol plays an essential role in the development of the PH phenotype (7)(8)(9). Estrogen can also induce proliferation of human pulmonary artery smooth muscle cell (hPASMCs) and may therefore contribute to the pulmonary artery remodeling observed in PAH (7,10).…”

Metformin Reverses Development of Pulmonary Hypertension via Aromatase Inhibition

“…[5][6][7][8] There is an estrogen paradox however as while exogenous estrogen may be protective against experimental pulmonary hypertension (PH) and right ventricular (RV) hypertrophy in rodent models, [9][10][11][12] endogenous estrogen is causative in female animal models. [13][14][15][16][17] Estrogen is synthesized from testosterone through the enzyme aromatase and inhibition of aromatase attenuates experimental PH but only in females. 17 Estrogen can be metabolized through the cytochrome p450 1B1 (CYP1B1) enzyme to form the mitogenic 16α-hydroxyestrone, a metabolite established to be pathogenic in PH.…”

A Sex-Specific MicroRNA-96/5-Hydroxytryptamine 1B Axis Influences Development of Pulmonary Hypertension

“…In addition, TPH-1 knockout mice are protected from hypoxia-induced pulmonary hypertension (PH) (10,11). We have shown that only female mice develop PH via a serotonin-dependent mechanism-for example, mice overexpressing the serotonin transporter (SERT), calcium-binding protein S100A4/mts1-overexpressing mice, and mice dosed with dexfenfluramine (6,12,13). This PH phenotype is estrogen dependent, and suggests that female sex and estrogen influence the development of PH in these serotonin-dependent models.…”