GPER mediates estrogen cardioprotection against epinephrine-induced stress

in Journal of Endocrinology
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  • 1 L Fu, physiology department, Xuzhou Medical University, Xuzhou, China
  • 2 H Zhang, physiology department, Xuzhou Medical University, Xuzhou, China
  • 3 J Machuki, physiology department, Xuzhou Medical University, Xuzhou, China
  • 4 T Zhang, physiology department, Xuzhou Medical University, Xuzhou, China
  • 5 L Han, physiology department, Xuzhou Medical University, Xuzhou, China
  • 6 L Sang, physiology department, Xuzhou Medical University, Xuzhou, China
  • 7 L Wu, physiology department, Xuzhou Medical University, Xuzhou, China
  • 8 Z Zhao, physiology department, Xuzhou Medical University, Xuzhou, China
  • 9 M Turley, National Heart and Lung Institute, Imperial College London, London, United Kingdom of Great Britain and Northern Ireland
  • 10 X Hu, physiology department, Xuzhou Medical University, Xuzhou, China
  • 11 H Hou, physiology department, Xuzhou Medical University, Xuzhou, China
  • 12 D Li, Institute of Cardiovascular Disease Research, Xuzhou Medical University, Xuzhou, China
  • 13 S Harding, National Heart and Lung Institute, Imperial College London, London, United Kingdom of Great Britain and Northern Ireland
  • 14 H Sun, physiology department, Xuzhou Medical University, Xuzhou, China

Correspondence: Hong Sun, Email: sunh@xzhmu.edu.cn
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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 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.

 

Society for Endocrinology