Oestrogen inhibition reverses pulmonary arterial hypertension and associated metabolic defects.

Chen X, Austin ED, Talati M, Fessel JP, Farber-Eger EH, Brittain EL, Hemnes AR, Loyd JE, West J
Eur Respir J. 2017 50 (2)

PMID: 28775043 · PMCID: PMC6532788 · DOI:10.1183/13993003.02337-2016

Increased oestrogen is a strong epidemiological risk factor for development of pulmonary arterial hypertension (PAH) in patients, associated with metabolic defects. In addition, oestrogens drive penetrance in mice carrying mutations in bone morphogenetic protein receptor type II (BMPR2), the cause of most heritable PAH. The goal of the present study was to determine whether inhibition of oestrogens was effective in the treatment of PAH in these mice.The oestrogen inhibitors fulvestrant and anastrozole were used in a prevention and treatment paradigm in BMPR2 mutant mice, and tamoxifen was used for treatment. In addition, BMPR2 mutant mice were crossed onto oestrogen receptor (ESR)1 and ESR2 knockout backgrounds to assess receptor specificity. Haemodynamic and metabolic outcomes were measured.Oestrogen inhibition both prevented and treated PAH in BMPR2 mutant mice. This was associated with reduction in metabolic defects including oxidised lipid formation, insulin resistance and rescue of peroxisome proliferator-activated receptor-γ and CD36. The effect was mediated primarily through ESR2, but partially through ESR1.Our data suggest that trials of oestrogen inhibition in human PAH are warranted, and may improve pulmonary vascular disease through amelioration of metabolic defects. Although fulvestrant and anastrozole were more effective than tamoxifen, tamoxifen may be useful in premenopausal females, because of a reduced risk of induction of menopause.

Copyright ©ERS 2017.

MeSH Terms (21)

Anastrozole Animals Bone Morphogenetic Protein Receptors, Type II Disease Models, Animal Echocardiography Estradiol Estrogen Antagonists Female Fulvestrant Hemodynamics Humans Hypertension, Pulmonary Insulin Resistance Lung Mice Mice, Knockout Mutation Nitriles Signal Transduction Tamoxifen Triazoles

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