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Improvement of Cardiovascular Function in Aging Females by the Prolonged Activation of G Protein-Coupled Estrogen Receptor

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Abstract

Ample evidence suggests that estrogen replacement therapy is associated with beneficial effects with regard to cardiovascular diseases when the therapy is initiated temporally close to menopause but not when it is initiated later. Little is known about the complex interactions between hormone receptors after menopause. Coronary artery function and cardiac function were measured in rats that had either received no treatment or had been pretreated with an androgen receptor (AR) antagonist and/or a GPER agonist G-1. ICI 182,780 was used to block the classical estrogen receptors (ERs) to investigate their complex interactions with GPER. The beneficial effects of GPER were only observed by blocking ARs and classical ERs in aged female rats. The results demonstrate that GPER activation is a potential therapeutic target for the inhibition of age-dependent coronary artery dysfunction and cardiac dysfunction under the condition of blocking ARs and classical ERs after menopause.

Clinical Relevance

The risk of cardiovascular disease in postmenopausal women significantly increased. The role of sex hormones and their receptors during this process is still complicated. Our present study demonstrated that the imbalance of androgen and estrogen may contribute to the impairment of vascular reactivity and subsequent cardiac function. Treatment with GPER agonist G1 combined with the inhibition of ERα and ERβ could improve vascular function and reduce the myocardial ischemia reperfusion injury. These findings may provide the novel and effective strategy for the treatment of cardiovascular diseases in postmenopausal women.

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Abbreviations

ACh:

Acetylcholine

AR:

Androgen receptor

CK:

Creatine kinase

DHE:

Dihydroethidium

ER:

Estrogen receptors

GPER:

G protein-coupled estrogen receptor

HRT:

Estrogen replacement therapy

LVDP:

Left ventricular diastolic pressure

LVEDP:

Left ventricular end-diastolic pressure

LVSP:

Left ventricular systolic pressure

PE:

Phenylephrine

ROS:

Reactive oxygen species

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

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Funding

This work was supported by the National Natural Science Foundation of China (82070264 82070503, 81400276), the China Postdoctoral Science Foundation (Grant No: 2013M542442), and the Key R&D Program of Shaanxi Province (2022ZDLSF01-09).

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Author notes

  1. Jipeng Ma, Jing Hu, and Xiaowu Wang contributed to this work equally.

Authors and Affiliations

  1. Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China

    Jipeng Ma, Xiaowu Wang, Shuaishuai Zhang, Zilin Li & Jincheng Liu

  2. Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Science & Medicine, Northwest University, Xi’an, China

    Jing Hu

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Contributions

JL and ZL conceived and designed the experiments; JM, JH, and XW performed the experiments; JH and SZ established the animal models; XW and ZL analyzed the data; JM, ZL, and JL wrote, revised, and checked the manuscript. All authors have reviewed the contents of the manuscript, validated the accuracy of the data, and approved the submitted manuscript.

Corresponding authors

Correspondence to Zilin Li or Jincheng Liu.

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Ethics Approval

The present study was performed in accordance with the National Institutes of Health guidelines for the use of experimental animals, and all animal protocols were approved by the Committee for Ethical Use of Experimental Animals of the Fourth Military Medical University (No: 20150107).

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The authors declare no competing interests.

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Associate Editor Nicola Smart oversaw the review of this article

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Ma, J., Hu, J., Wang, X. et al. Improvement of Cardiovascular Function in Aging Females by the Prolonged Activation of G Protein-Coupled Estrogen Receptor. J. of Cardiovasc. Trans. Res. 16, 371–381 (2023). https://doi.org/10.1007/s12265-022-10315-z

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