GPER-1 and Estrogen Receptor-β Ligands Modulate Aldosterone Synthesis

• DOI: 10.1210/en.2014-1416
• Publication Date: 2014-08-28T16:48:23Z
• Authors: Brasilina Caroccia; Teresa M. Seccia; Abril Gonzalez Ca...; Francesca Gioco; Maniselvan Kuppusamy; Giulio Ceolotto; Eugenia Guerzoni; Francesca Simonato; Sara Mareso; Livia Lenzini; Ambrogio Fassina; Gian Paolo Rossi
• Keywords: GPER; Aldosterone synthase; Mineralocorticoid

Abstract Fertile women have lower blood pressure and cardiovascular risk than age-matched men, which suggests that estrogens exert protective effects. However, whether 17 β-estradiol (E2) blunts aldosterone secretion, thereby affects the gender dimorphism of pressure, is unknown. We therefore sought for estrogen receptor (ER) subtypes in human adrenocortical tissues ex vivo by performing gene protein expression studies. also investigated effect E2 on synthesis involved receptors through vitro functional experiments cells HAC15. found adrenal cortex aldosterone-producing adenoma cells, most expressed ERs were ERβ G protein-coupled receptor-1 (GPER-1), respectively. After selective blockade, (10 nmol/L) markedly increased both synthase production (+5- to 7-fold vs baseline, P < .001). Under same condition, GPER-1 agonist 1-[4-(6-bromo-benzo (1, 3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c] quinolin-8-yl]-ethanone (G-1) mimicked this effect, was abrogated cotreatment with either antagonist (3aS*,4R*,9bR*)-4-(6-Bro-mo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta[c]quinoline (G-15), or a kinase A inhibitor 8-Bromo-2-monobutyryladenosine-3,5-cyclic mono-phosphorothioate, Rp-isomer. Silencing significantly raised production. Conversely, silencing lowered expression. Moreover, it blunted stimulatory seen during blockade. These results support conclusion humans, inhibits acting via ERβ. Pharmacologic disinhibition unmasks potent secretagogue involves signaling.