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17β-Estradiol and/or estrogen receptor alpha blocks isoproterenol-induced calcium accumulation and hypertrophy via GSK3β/PP2A/NFAT3/ANP pathway

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Abstract

The present study was aimed to investigate the protective effects of 17β-estradiol (E2) and estrogen receptor α (ERα) on isoproterenol (ISO)-treated H9c2 cardiomyoblast cells. In the present study, we treated H9c2 cells with ISO, a β-adrenergic receptor agonist, to induce myocardiac hypertrophy. Pre-administration of E2 or ERα (induced by doxycycline) and E2 plus ERα significantly prevented ISO-induced increase of cell size and cytosolic calcium accumulation, accompanied with increased mRNA of atrial natriuretic peptide and brain natriuretic peptide. However, ICI-ERs antagonist, and melatonin, a specific inhibitor for ERα, reversed the cardioprotective effects, suggesting that E2 action was mediated through ERα. Further evidences showed that E2 and ERα increased the protein level of GSK3β and protein phosphatase 2a inhibitor 2 (I2-PP2A), which subsequently enhanced the activation of I2-PP2A by disrupting PP2A activity and maintains normal calcium outflow. Collectively, E2 and ERα inhibited hypertrophy by preventing cytosol calcium accumulation and by inhibiting the association between PP2A with Na+–Ca2+ exchanger via GSK3β and I2-PP2A activation.

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Acknowledgements

This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence: MOHW105-TDU-B-212-133019.

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  1. Peiying Pai, Bharath Kumar Velmurugan and Chia-Hua Kuo have contributed equally to this paper.

Authors and Affiliations

  1. Division of Cardiology, China Medical University Hospital, Taichung, Taiwan

    Peiying Pai, Bharath Kumar Velmurugan, Chia-Hua Kuo, Chung-Yi Yen, Tsung-Jung Ho, Yueh-Min Lin, Yu-Feng Chen, Chao-Hung Lai, Cecilia Hsuan Day & Chih-Yang Huang

  2. Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam

    Bharath Kumar Velmurugan

  3. Department of Sports Sciences, University of Taipei, Taipei, Taiwan

    Chia-Hua Kuo

  4. Graduate Institute of Basic Medical Science, School of Chinese Medicine, China Medical University and Hospital, 91 Hsueh-Shih Road, Taichung, 404, Taiwan, ROC

    Peiying Pai, Chung-Yi Yen & Chih-Yang Huang

  5. Chinese Medicine Department, China Medical University Beigang Hospital, Beigang, Taiwan

    Tsung-Jung Ho

  6. Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan

    Tsung-Jung Ho & Chih-Yang Huang

  7. Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan

    Yueh-Min Lin

  8. Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan

    Yueh-Min Lin

  9. Section of Cardiology, Yuan Rung Hospital, Yuanlin, Taiwan

    Yu-Feng Chen

  10. Division of Cardiology, Department of Internal Medicine, Armed Force Taichung General Hospital, Taichung, Taiwan

    Chao-Hung Lai

  11. Department of Nursing, MeiHo University, Pingtung, Taiwan

    Cecilia Hsuan Day

  12. Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan

    Chih-Yang Huang

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  1. Peiying Pai
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Pai, P., Velmurugan, B.K., Kuo, CH. et al. 17β-Estradiol and/or estrogen receptor alpha blocks isoproterenol-induced calcium accumulation and hypertrophy via GSK3β/PP2A/NFAT3/ANP pathway. Mol Cell Biochem 434, 181–195 (2017). https://doi.org/10.1007/s11010-017-3048-3

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