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SOX2-mediated inhibition of miR-223 contributes to STIM1 activation in phenylephrine-induced hypertrophic cardiomyocytes

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Abstract

Stromal interaction molecule 1 (STIM1) is the key molecule responsible for store-operated Ca2+ entry (SOCE). Numerous studies have demonstrated that STIM1 levels appeared to be enhanced during cardiac hypertrophy. However, the mechanism underlining this process remains to be clarified. In this study, phenylephrine (PE) was employed to establish a model of hypertrophic neonatal rat cardiomyocytes (HNRCs) in vitro, and low expression of primary and mature miR-223 was detected in PE-induced HNRCs. Our results have revealed that downregulation of miR-223 by PE contributed to the increase of STIM1, which in turn induced cardiac hypertrophy. As expected, overexpression of miR-223 could prevent the increase in cell surface and reduce the mRNA levels of ANF and BNP in cardiomyocytes. To address the mechanism triggering downregulation of miR-223 under PE, we demonstrated that PE-induced inhibition of GSK-3β activity led to the activation of β-catenin, which initiates the transcription of SOX2. Increased expression of SOX2 occupied the promoter region of primary miR-223 and suppressed its transcription. Therefore, miR-223 appears to be a promising candidate for inhibiting cardiomyocyte hypertrophy, and miR-223/STIM1 axis might be one of interesting targets for the clinical treatment of hypertrophy.

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Acknowledgements

This study was supported by the Chinese Natural Science Foundation Grants (81303132), the Science and Technology Development Special Fund of Shanghai Health and Family Planning Commission (ZK2015A17), the Science and Technology Development Special Fund of Zhoupu Hospital (ZP2014A-01).

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  1. Zhi-Hong Zhao and Jun Luo contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Shanghai Pudong New Area Zhoupu Hospital, Shanghai University of Medicine & Health Sciences, 1500 Zhouyuan Road, Shanghai, 201318, People’s Republic of China

    Zhi-Hong Zhao, Jun Luo, Sai-hua Wang & Xin-ming Li

  2. Department of Cardiology, Guang Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China

    Hai-xia Li

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  1. Zhi-Hong Zhao
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11010_2017_3209_MOESM3_ESM.pdf

Supplementary material 3 Supplementary Figure 1. miR-223 expression value in neonatal rat cardiomyocytes from 5-day TCA induction model (GEO/GSE38599). Supplementary Figure 2. Mature miR-223 expression level was examined by qPCR after infection of mir-223. (PDF 921 kb)

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Zhao, ZH., Luo, J., Li, Hx. et al. SOX2-mediated inhibition of miR-223 contributes to STIM1 activation in phenylephrine-induced hypertrophic cardiomyocytes. Mol Cell Biochem 443, 47–56 (2018). https://doi.org/10.1007/s11010-017-3209-4

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