GPER mediates estrogen cardioprotection against epinephrine-induced stress

in Journal of Endocrinology
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  • 1 Physiology Department, Xuzhou Medical University, Xuzhou, Jiangsu, China
  • 2 National Heart and Lung Institute, Imperial College London, UK
  • 3 Institute of Cardiovascular Disease Research, Xuzhou Medical University, Xuzhou, Jiangsu, China

Correspondence should be addressed to H Sun: sunh@xzhmu.edu.cn

*(L Fu and H Zhang contributed equally to this work)

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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 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, 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 signaling pathways.

Supplementary Materials

    • Supplement Fig. 1 Changes in cardiomyocyte shortening amplitude after treatment with Epi (100 nmol /L, 20 min). Data shown are mean &#x00B1; S.E.M. n = 3-10 rats, at least 10 myocytes per experimental group per rat heart were studied. All outliers have been included. **P < 0.01 vs control. #P<0.05 vs Epi at 20 min; $P<0.05 vs E2+Epi at 20 min.
    • Supplementary Fig 2. Detection of &#x03B2;2AR by immunofluorescence after Epi treatment in hiPSC-CMs(100 nmol /L, 20 min), a: control, b: Epi, c: E2+Epi, d: G1+Epi, e: G15+E2+Epi. The scale is 50&#x03BC;m.
    • Supplementary Fig. 3 GPER gene expression in hiPSC-CM knockdown with siRNA. Data shown are mean &#x00B1; S.E.M. n=4. *P < 0.01 vs Control.

 

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