GPER mediates estrogen cardioprotection against epinephrine-induced stress

Abstract

Currently, there are no conventional treatments for stress-induced cardiomyopathy (SCM, also known as Takotsubo syndrome), and the existing therapies are not effective. The recently discovered G protein- coupled estrogen receptor (GPER) executes the rapid effects of estrogen (E2). In this study, we investigated the effects and mechanism of GPER on epinephrine (Epi)-induced cardiac stress. SCM was developed with a high dose of Epi in adult rats and human-induced pluripotent stem cells–derived cardiomyocytes(hiPSC-CMs). (1) GPER activation with agonist G1/ E2 prevented an increase in left ventricular internal diameter at end-systole, the decrease both in ejection fraction and cardiomyocyte shortening amplitude elicited by Epi. (2) G1/ E2 mitigated heart injury induced by Epi, as revealed by reduced plasma brain natriuretic peptide and lactate dehydrogenase release into culture supernatant. (3) G1/E2 prevented the raised phosphorylation and internalization of β2-adrenergic receptors（β2AR）. (4) Blocking Gαi abolished the cardiomyocyte contractile inhibition by Epi. G1/E2 downregulated Gαi activity of cardiomyocytes and further upregulated cyclic adenosine monophosphate concentration in culture supernatant treated with Epi. (5) G1/E2 rescued decreased Ca2+ amplitude and Ca2+ channel current (ICa-L) in rat cardiomyocytes. Notably, the above effects of E2 were blocked by the GPER antagonist, G15. In hiPSC-CM (which expressed GPER, β1AR and β2ARs), knockdown of GPER by siRNA abolished E2 effects on increasing ICa-L and action potential duration in the stress state. In conclusion, GPER played a protective role against SCM. Mechanistically, this effect was mediated by balancing the coupling of β2AR to the Gαs and Gαi signalling pathways.

Estrogens for protection from an index and recurrent episodes of takotsubo syndrome?

“…As the authors state there are no 'conventional' such therapies, and what are available 'are not effective' (1); if one considers TTS as a malady associated with a transiently 'stunned' myocardium, some other therapies designed for ischemic coronary syndromes, including acute myocardial infarction have been recently proposed, and may need to be evaluated and tried in patients with TTS (Madias 2021). The authors (Fu et al 2021) report on the protective mechanism of the G protein-coupled estrogen receptor (GPER) activation on the epinephrine (Epi)-induced TTS, employing their adult rat model and a human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CM) preparation; their work echoes some of the findings of Ueyama et al (2003), Ueyama (2007), dated almost 20 years ago. Such investigations only explain why TTS emerges mainly in women and particularly of the postmenopausal age, and reveals that estrogens exert a cardioprotective effect, preventing the emergence of TTS (Ueyama et al 2003, Ueyama 2007, Fu et al 2021, which is very important from the pathogenesis point of view.…”

“…The authors (Fu et al 2021) report on the protective mechanism of the G protein-coupled estrogen receptor (GPER) activation on the epinephrine (Epi)-induced TTS, employing their adult rat model and a human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CM) preparation; their work echoes some of the findings of Ueyama et al (2003), Ueyama (2007), dated almost 20 years ago. Such investigations only explain why TTS emerges mainly in women and particularly of the postmenopausal age, and reveals that estrogens exert a cardioprotective effect, preventing the emergence of TTS (Ueyama et al 2003, Ueyama 2007, Fu et al 2021, which is very important from the pathogenesis point of view. Although estrogen therapy is not currently recommended, particularly for women in their 60s and 70s, the time period during which postmenopausal women are at high risk to develop TTS, one wonders whether lowdose or transdermal estrogens (Pinkerton 2020) may have a protective effect on the occurrence of TTS, or after an index episode of TTS, prevention of its recurrence(s).…”

“…The fascinating article of Fu et al (2021), published in the June 2021 issue of Journal of Endocrinology pages 209-222, brings up again the vexing problems of prevention and therapy of takotsubo syndrome (TTS) (Madias 2019(Madias , 2021. As the authors state there are no 'conventional' such therapies, and what are available 'are not effective' (1); if one considers TTS as a malady associated with a transiently 'stunned' myocardium, some other therapies designed for ischemic coronary syndromes, including acute myocardial infarction have been recently proposed, and may need to be evaluated and tried in patients with TTS (Madias 2021).…”

“…The authors showed that the GPER activation with agonist G1/ E2 prevented the increase in the end-systolic left ventricular internal diameter and the decrement of the left ventricular ejection fraction in their rat model, and the shortening of the hiPSC-CM amplitude, among a large host of other supportive findings of G1/E2-induced cardioprotection in Epi-elicited TTS (1). Relevant to the above therapy proposition of low-dose estrogens for the prevention of TTS in women is whether, experiments employing the author's rat model, a dose of 12 μg/100 g or 24 μg/100 g, instead of the used 48 μg/100 g G1 (Fu et al 2021), exerts a significant cardioprotective effect if administered 10 min prior to the Epi-elicited TTS. Even more relevant to the human TTS may be an implementation of the authors' model of adult rats (Fu et al 2021), but after the rats are ovariectomized, and while they are receiving chronic estrogen supplementation (Ueyama et al 2007), in lowdoses, prior to Epi-elicitation of TTS.…”

“…Relevant to the above therapy proposition of low-dose estrogens for the prevention of TTS in women is whether, experiments employing the author's rat model, a dose of 12 μg/100 g or 24 μg/100 g, instead of the used 48 μg/100 g G1 (Fu et al 2021), exerts a significant cardioprotective effect if administered 10 min prior to the Epi-elicited TTS. Even more relevant to the human TTS may be an implementation of the authors' model of adult rats (Fu et al 2021), but after the rats are ovariectomized, and while they are receiving chronic estrogen supplementation (Ueyama et al 2007), in lowdoses, prior to Epi-elicitation of TTS. I will greatly appreciate the response of the authors on the above.…”