• Open Access

GATA4 regulates ANF expression synergistically with Sp1 in a cardiac hypertrophy model

Authors

  • Xiaoqing Hu,

    1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, Haidian District, Beijing, China
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    • Both contributed equally to this work.

  • Tao Li,

    1. Department of Biology, College of Chemistry and Life Science, Zhejiang Normal University, Jinhua, Zhejiang Province, China
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    • Both contributed equally to this work.

  • Chenguang Zhang,

    1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, Haidian District, Beijing, China
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  • Yinan Liu,

    1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, Haidian District, Beijing, China
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  • Ming Xu,

    1. Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China
    2. Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, Beijing, China
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  • Weiping Wang,

    1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, Haidian District, Beijing, China
    2. Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, Beijing, China
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  • Zhuqing Jia,

    1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, Haidian District, Beijing, China
    2. Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, Beijing, China
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  • Kangtao Ma,

    1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, Haidian District, Beijing, China
    2. Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, Beijing, China
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  • Youyi Zhang,

    1. Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China
    2. Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, Beijing, China
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  • Chunyan Zhou

    Corresponding author
    1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, Haidian District, Beijing, China
    2. Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education of China, Peking University, Beijing, China
      Chunyan ZHOU, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China Tel.: +86-10-82802417Fax: +86-10-82802417 Email: chunyanzhou@bjmu.edu.cn
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Chunyan ZHOU, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China Tel.: +86-10-82802417Fax: +86-10-82802417 Email: chunyanzhou@bjmu.edu.cn

Abstract

Cardiac hypertrophy in response to multiple stimuli has important physiological and pathological significances. GATA4 serves as a nuclear integrator of several signalling pathways during cardiac hypertrophy. Sp1 and Sp3 are also reported to be involved in this process. However, the mechanism by which GATA4 acts as a mediator, integrating these ubiquitously expressed transcriptional factors, is poorly understood. We found that the expression of GATA4 and Sp1 was up-regulated in the myocardium of a pressure overload hypertrophy rat model, as well in phenylephrine-induced (PE-induced) hypertrophic growth of neonatal cardiomyocytes. GST pull-down assays demonstrated that GATA4 could interact with Sp1 in vitro. Therefore, we proposed that GATA4 cooperates with Sp1 in regulating ANF expression, as its reactivation is closely linked with hypertrophy. Further studies demonstrated that GATA4 could activate the ANF promoter synergistically with Sp1 through direct interaction. In contrast, Sp3 exhibited antagonistic function, and overexpression of Sp3 repressed the transcriptional synergy between Sp1 and GATA4. We also found that Sp1 alone could activate the ANF promoter in cardiomyocytes, whereas Sp3 exerted negative effects on ANF expression. Bioinformatics analysis revealed novel Sp-binding sites on the ANF promoter. The recruitment of GATA4 and Sp1 on the ANF promoter was enhanced during phenylephrine-mediated hypertrophy, whereas the recruitment of Sp3 was reduced. The phosphorylation of GATA4 by ERK1/2 kinase could enhance the affinity between GATA4 and Sp1. Thus, our findings revealed the critical interaction of GATA4 and Sp1 in modulating ANF expression, indicating their involvement in cardiac hypertrophy.

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