{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:56:21Z","timestamp":1790704581527,"version":"4.1.0"},"reference-count":62,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2018,3,1]]},"abstract":"<jats:p> Estradiol (E<jats:sub>2<\/jats:sub>) prevents cardiac hypertrophy, and these protective actions are mediated by estrogen receptor (ER)\u03b1 and ER\u03b2. The G protein-coupled estrogen receptor (GPER) mediates many estrogenic effects, and its activation in the heart has been observed in ischemia and reperfusion injury or hypertension models; however, the underlying mechanisms need to be fully elucidated. Herein, we investigated whether the protective effect of E<jats:sub>2<\/jats:sub> against cardiomyocyte hypertrophy induced by endothelin-1 (ET-1) is mediated by GPER and the signaling pathways involved. Isolated neonatal female rat cardiomyocytes were treated with ET-1 (100 nmol\/l) for 48 h in the presence or absence of E<jats:sub>2<\/jats:sub> (10 nmol\/l) or GPER agonist G-1 (10 nmol\/l) and GPER antagonist G-15 (10 nmol\/l). ET-1 increased the surface area of cardiomyocytes, and this was associated with increased expression of atrial and brain natriuretic peptides. Additionally, ET-1 increased the phosphorylation of extracellular signal-related protein kinases-1\/2 (ERK1\/2). Notably, E<jats:sub>2<\/jats:sub> or G-1 abolished the hypertrophic actions of ET-1, and that was reversed by G-15. Likewise, E<jats:sub>2<\/jats:sub> reversed the ET-1-mediated increase of ERK1\/2 phosphorylation as well as the decrease of phosphorylated Akt and its upstream activator 3-phosphoinositide-dependent protein kinase-1 (PDK1). These effects were inhibited by G-15, indicating that they are GPER dependent. Confirming the participation of GPER, siRNA silencing of GPER inhibited the antihypertrophic effect of E<jats:sub>2<\/jats:sub>. In conclusion, E<jats:sub>2<\/jats:sub> plays a key role in antagonizing ET-1-induced hypertrophy in cultured neonatal cardiomyocytes through GPER signaling by a mechanism involving activation of the PDK1 pathway, which would prevent the increase of ERK1\/2 activity and consequently the development of hypertrophy. <\/jats:p>","DOI":"10.1152\/ajpcell.00060.2017","type":"journal-article","created":{"date-parts":[[2017,11,22]],"date-time":"2017-11-22T21:00:16Z","timestamp":1511384416000},"page":"C310-C322","source":"Crossref","is-referenced-by-count":26,"title":["Neonatal cardiomyocyte hypertrophy induced by endothelin-1 is blocked by estradiol acting on GPER"],"prefix":"10.1152","volume":"314","author":[{"given":"Gleisy Kelly","family":"Goncalves","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 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