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Estrogen deficiency compromised the β2AR-Gs/Gi coupling: implications for arrhythmia and cardiac injury

  • Signaling and cell physiology
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Abstract

Estrogen and β2-adrenergic receptors (β2AR) play important roles in the processes that protect the heart. Here, we investigated how ovariectomy influenced the β2AR downstream pathways in the context of catecholaminergic stress. In vivo and in vitro stress models were developed in female Sprague-Dawley (SD) rats by epinephrine (Epi) treatments. The cardiac function was evaluated at in vivo and in vitro levels in terms of contraction, rhythm, and injury. We found that myocardial contractility was not significantly different between Sham and ovariectomized (OVX) group rats in the normal state. However, Epi pretreatment decreased the contractility and increased abnormal rhythms especially in OVX group, which were attributed to lack of estrogen. Inhibition of the β2AR-Gi-PI3K/p38MAPK pathway with ICI118,551, PTX or LY294002 increased contractility and aggravated Epi-induced injury on cardiomyocytes, decreased p38MAPK phosphorylation, and only increased arrhythmia in Sham group. These results indicated that OVX exacerbated cardiac injury and abnormal rhythms through β2AR-Gi-PI3K and β2AR-Gi-p38MAPK pathways, respectively. In normal state, the levels of activated Gi were similar in both groups, but those of cAMP and activated Gs were higher in OVX group. Epi treatment increased activated Gi (especially in Sham group) and activated Gs and cAMP in Sham group but decreased it in OVX group. These results suggested that estrogen increased the Gi activity in normal and stress states and Gs activity in stress state. These results indicated that lack of estrogen impaired the β2AR-Gs/Gi coupling during stress which compromised cardiac contractility and increased abnormal rhythms.

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Abbreviations

AC:

adenylyl cyclase

BNP:

brain natriuretic peptide

β1AR:

β1-adrenoceptor

β2AR:

β2-adrenoceptor

Epi:

epinephrine

EF:

left ventricular ejection fraction

Gs:

stimulatory G proteins

Gi:

inhibitory G proteins

ISO:

isoprenaline

LDH:

lactic dehydrogenase

LVIDd:

left ventricular internal diameters at End-diastolic dimension

LVIDs:

left ventricular internal diameters at End-systolic dimension

OVX:

ovariectomy

p38 MAPK:

p38 mitogen-activated protein kinase

PKA:

protein kinase A

PI3K:

phosphoinositide 3-kinase

TCM:

Takotsubo cardiomyopathy

VPB:

ventricular premature beat

VT:

ventricular tachycardia

VF:

ventricular fibrillation

Epac :

exchange protein directly activated by cAMP

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Funding

This work was supported by the National Natural Science Foundation of China (No.81370329, No.81461138036) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Author notes

  1. Hongjian Hou and Zhiwei Zhao contributed equally to this work.

Authors and Affiliations

  1. Physiology Department, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China

    Hongjian Hou, Jeremiah Ong’achwa Machuki, Lin Zhang, Yan Zhang, Lu Fu, Jinxia Wu & Hong Sun

  2. Institute of Cardiovascular Disease Research, Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China

    Zhiwei Zhao & Yuyu Liu

  3. Myocardial Function Section, National Heart and Lung Institute, Imperial College London, London, UK

    Sian E. Harding

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  1. Hongjian Hou
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Correspondence to Hong Sun.

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All studies complied with the Animal Ethics Committee of Xuzhou Medical University (permit number: xz11-12540) and with the Guideline for the Care and Use of Laboratory Animals published by the US National Institutes of health (NIH Publication, 8th Edition, 2011).

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Hou, H., Zhao, Z., Machuki, J.O. et al. Estrogen deficiency compromised the β2AR-Gs/Gi coupling: implications for arrhythmia and cardiac injury. Pflugers Arch - Eur J Physiol 470, 559–570 (2018). https://doi.org/10.1007/s00424-017-2098-4

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