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 ß2-adrenergic receptors (ß2AR). (4) Blocking Gαi abolished the cardiomyocyte contractile inhibition by Epi. G1/E2 downregulated Gαi activity of cardiomyocytes and further upregulated cAMP 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, ß1AR and ß2ARs), 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 ß2AR to the Gαs and Gαi signaling pathways.
