Anti‐Hypertrophic Effect of Estradiol in Cardiomyocytes is Mediated by GPER1

Previous data have shown that E2 prevents cardiomyocyte hypertrophy induced by endothelin‐1 (ET‐1) and Angiotensin II, acting through the increase of atrial and type‐B natriuretic peptides (ANP and BNP) levels. In recent years, a membrane‐bound E2 receptor has emerged, G protein‐coupled estrogen receptor 1 (GPER1), which mediates many estrogenic effects. In this work, we investigated whether E2 protective signaling effect on ET1‐induced hypertrophy is mediated via GPER1 receptor. Newborn rat cardiomyocytes were isolated and cultured in DMEM supplemented with 10% fetal bovine serum with antibiotic and antimycotic. Cells were treated for 48h with ET‐1 (10 nM) in the presence or not of E2 (10 nM). In some experiments GPER1 antagonist (G15, 10 nM) was added to the medium. ET‐1 induced an increase in cardiac myocyte area compared to control group. Treatment with E2 partially inhibited the hypertrophic effect of ET‐1. Treatment with G15 reversed antihypertrophic effect of E2. Moreover, ET‐1 upregulated ANP and BNP levels, an effect that was abolished by E2. G15 prevented the decrease of BNP but not ANP in cardiomyocytes treated with E2 in the presence of ET‐1. ET‐1 treated cells showed increased translocation of GRK5 to the nucleus and this effect was abolished by E2. The reduction of the contraction frequency and increase of contraction force observed in the ET‐1 group were reversed by E2. In conclusion, E2 plays a key role antagonizing the hypertrophy induced by ET1 and this effect was mediated by GPER1. Financial Support: CNPQ, CAPES, FAPEMIG