Neonatal cardiomyocyte hypertrophy induced by endothelin-1 is blocked by estradiol acting on GPER

Abstract

Estradiol (E) prevents cardiac hypertrophy, and these protective actions are mediated by estrogen receptor (ER)α and ERβ. 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 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 (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 or G-1 abolished the hypertrophic actions of ET-1, and that was reversed by G-15. Likewise, E 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. In conclusion, E 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.

Estrogen Attenuates Chronic Stress-Induced Cardiomyopathy by Adaptively Regulating Macrophage Polarizations via β2-Adrenergic Receptor Modulation

“…Nevertheless, E 2E ndo (in the Sham rats) showed much potency at minimizing the upregulations of both ANP and BNP during stress, while E 2E xo (in the OVX + E 2 rats) was unable to downregulate the latter substantially. In conformity with our findings, Goncalves et al (2018) and others had early demonstrated that E 2 exerts antihypertrophic effects via GPER ( Goldstein et al, 2004 ). Also, the discrepancies observed between the antihypertrophic effect of E 2E ndo and E 2E xo might have occurred because other ovarian secretions such as vascular endothelial growth factor (VEGF) may complement the efforts of E 2 in preventing maladaptive cardiomyocyte hypertrophy ( Cai et al, 2015 ).…”

Effects and safety of Psilocybe cubensis and Panaeolus cyanescens magic mushroom extracts on endothelin-1-induced hypertrophy and cell injury in cardiomyocytes

“…The H9C2 cardiomyoblast cells were cultured according to the method of 18,32 with modification. Briefly as soon as cells reached 70% confluency they were passaged, counted and 1 × 10 6 cells seeded and grown on glass cover slips in 6 well plates (NEST, Whitehead scientific).…”

G protein-coupled estrogen receptor 1 regulates renal endothelin-1 signaling system in a sex-specific manner

“…However, estradiol treatment to OVX SD rats eliminates the OVX-induced increase in renal ET A and ET B receptor expression ( Gohar et al, 2016b ), pointing to estrogen as a regulator for renal ET receptor expression. Indeed, evidence suggest a potential crosstalk between GPER1 and ET-1 signaling pathways within the vascular ( Meyer et al, 2012 ), cardiac ( Goncalves et al, 2018 ), and renal systems ( Gohar et al, 2020 ; Gohar and Pollock, 2021 ). Within the renal medulla of the female SD rat, G1-induced natriuresis is blunted by simultaneous ET A and ET B inhibition ( Gohar et al, 2020 ; Gohar and Pollock, 2021 ), which provides supporting evidence that GPER1 is a female-specific pro-natriuretic factor due to its interactions with the renal ET-1 system, yet these signaling interactions are not completely understood.…”