Abstract 359: Modulation of Aldosterone Synthase by Estrogens: Evidence for an Interaction of Gper-1 and Estrogen B Receptors and Relevance for the Gender Dimorphism of Blood Pressure
Background. Fertile women have lower blood pressure and are held to be at lower risk for cardiovascular events than age-matched man. However, whether this gender dimorphism involves a modulation of aldosterone synthesis by 17 beta-estradiol (E2) is unknown.
Aims. i) To investigate estrogen receptor subtypes gene expression in the normal human adrenal cortex (NAC), in aldosterone producing adenoma (APA) and in a human adrenocortical carcinoma cell line (HAC15); ii) To assess the effect of E2 on aldosterone synthase (CYP11B2) gene expression and to identify the receptor subtypes involved in this effect.
Methods. We measured the expression of alpha (ERa), beta (ERb) and of G protein-coupled receptor (GPER-1)-1 in NAC and in APA tissue, and in HAC15 cells by real time RT-PCR. After demonstration that HAC15 cells express ERa, ERb, and GPER-1 we stimulated cells with 10-7M E2 alone, or after ERb selective blockade with 10-5M tetrahydrochrysenediol (THC), ERa selective blockade with 10-5M MPP dihydrochloride (MPP), non selective ERa and ERb blockade with 10-5M ICI 182.780, or after selective GPER-1 receptor blockade with 10-5M G-15. The cells were also exposed to the GPER-1 agonist G-1, alone or in the presence of MPP, THC, or Fulvestrant, and/or G-15. Changes of expression of CYP11B2 mRNA, measured with RT RT-PCR, was the experimental endpoint.
Results. The quantitative expression of estrogen receptor subtypes was ERb > GPER-1 >> ERα in NAC, GPER-1 > ERb> ERa in APA, and ERb>ERa=GPER-1 in HAC15 cells. E2 alone or on top of selective ERa antagonism did not alter CYP11B2 expression. By contrast, E2 significantly increased CYP11B2 expression (+500 to + 700% from baseline, p <0.001) after selective ERb antagonism, or combined ERa and ERb blockade. Likewise, G-1 markedly increased CYP11B2 gene after combined ERb blockade, an effect that was abolished by G15 co-treatment.
Conclusion. E2 potently stimulates aldosterone synthase expression via GPER-1 subtype receptor activation when the ERb is blocked. The ERb-mediated tonic inhibition of aldosterone synthase could contribute to explaining both the lower BP and CV risk of fertile women and the increase of BP after when this tonic ERb-mediated inhibition wanes during menopause or estrogen-modulation treatment.
- © 2013 by American Heart Association, Inc.