期刊
JOURNAL OF ENDOCRINOLOGY
卷 249, 期 3, 页码 209-222出版社
BIOSCIENTIFICA LTD
DOI: 10.1530/JOE-20-0451
关键词
G-protein estrogen receptor; stress-induced cardiomyopathy; cardioprotection; hiPSC-CM
资金
- National Natural Science Foundation of China [81461138036, 81370329]
- UK Medical Research Council [MR/M010422/1]
- Natural Science Foundation of The Jiangsu Higher Education Institutes of China [17KJB180016]
- Postgraduate Research & Practice Innovation Program of Jiangsu Province [KYCX20-2447, KYCX17-1712, KYCX18-2167]
The study found that GPER can protect the heart from stress-induced cardiomyopathy by modulating the coupling of beta(2)-adrenergic receptors to G alpha s and G alpha i signaling pathways.
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 beta(2)-adrenergic receptors (beta(2)AR). (4) Blocking G alpha i abolished the cardiomyocyte contractile inhibition by Epi. G1 /E2 downregulated G alpha i 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, beta(1)AR and beta(2)ARs), 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 beta(2)AR to the G alpha s and G alpha i signaling pathways.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据