Estrogen rescues heart failure through estrogen receptor Beta activation

Abstract

BackgroundRecently, we showed that exogenous treatment with estrogen (E2) rescues pre-existing advanced heart failure (HF) in mice. Since most of the biological actions of E2 are mediated through the classical estrogen receptors alpha (ERα) and/or beta (ERβ), and both these receptors are present in the heart, we examined the role of ERα and ERβ in the rescue action of E2 against HF.MethodsSevere HF was induced in male mice by transverse aortic constriction-induced pressure overload. Once the ejection fraction (EF) reached ~ 35%, mice were treated with selective agonists for ERα (PPT, 850 μg/kg/day), ERβ (DPN, 850 μg/kg/day), or E2 (30 μg/kg/day) together with an ERβ-antagonist (PHTPP, 850 μg/kg/day) for 10 days.ResultsEF of HF mice was significantly improved to 45.3 ± 2.1% with diarylpropionitrile (DPN) treatment, but not with PPT (31.1 ± 2.3%). E2 failed to rescue HF in the presence of PHTPP, as there was no significant improvement in the EF at the end of the 10-day treatment (32.5 ± 5.2%). The improvement of heart function in HF mice treated with ERβ agonist DPN was also associated with reduced cardiac fibrosis and increased cardiac angiogenesis, while the ERα agonist PPT had no significant effect on either cardiac fibrosis or angiogenesis. Furthermore, DPN improved hemodynamic parameters in HF mice, whereas PPT had no significant effect.ConclusionsE2 treatment rescues pre-existing severe HF mainly through ERβ. Rescue of HF by ERβ activation is also associated with stimulation of cardiac angiogenesis, suppression of fibrosis, and restoration of hemodynamic parameters.

Oestrogen Receptor β Activation Protects Against Myocardial Infarction via Notch1 Signalling

“…This phenomenon may indicate that the specific and potent activation of oestrogen receptor β, rather than a simple increase in the number of its molecules, is what is required for the treatment of MI injury. In recent years, with the technological development of the synthesis of chemical compounds, many studies have used DPN as a specific oestrogen receptor β agonist [13,26]. Therefore, in the current study, we determined the role of oestrogen receptor β in MI-induced cardiac injury by means of its specific agonist DPN.…”

“…DPN and DAPT were initially dissolved in dimethyl sulfoxide and then diluted in sterile saline (final dimethyl sulfoxide concentration < 2%). The doses of DPN and DAPT were chosen according to previous studies [13,26,27]. Post-infarction remodelling has been peremptorily divided into an early phase (within 72 h) and a late phase.…”

The Role of Estrogen Receptors in Cardiovascular Disease

“…The cardioprotective role of ERβ has been highlighted in the recent years [ 88 , 89 ]. Isolated female mouse hearts lacking ERβ are less protected against I/R injury compared to wild-type female mice [ 88 ].…”

“…The cardioprotective role of ERβ has been highlighted in the recent years [ 88 , 89 ]. Isolated female mouse hearts lacking ERβ are less protected against I/R injury compared to wild-type female mice [ 88 ]. Activation of ERβ via a specific ERβ agonist prior to I/R has been shown to improve cardiac recovery by decreasing apoptosis and preserving mitochondrial integrity in female mice in vivo [ 90 ].…”

Peer Review #1 of "Effects of the loss of estrogen on the heart’s hypertrophic response to chronic left ventricle volume overload in rats (v0.1)"

“…E2 has been shown to rescue male mice with heart failure from transverse aortic constriction (a pressure overload model) via in part the ERbeta receptor and GPER. Iorga et al (2016)Iorga et al (2018 In the ACF model, estrogen therapy in males was able to reduce the hypertrophic response to the volume overload. Gardner et al (2009) It would be interesting in the future, to investigate E2 effects in male AR animals in order to know if their effect could be more beneficial than in females.…”