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Zinc finger and BTB domain-containing protein 20 aggravates angiotensin II-induced cardiac remodeling via the EGFR-AKT pathway

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Abstract

Zinc finger and BTB domain-containing protein 20 (ZBTB20) play an important role in glucose and lipid homeostasis. ZBTB20 was shown to be a crucial protein for the maintenance of cardiac contractile function. However, the role of ZBTB20 in cardiac response remodeling has not been elucidated. Thus, this study aimed to explore the role of ZBTB20 in cardiac remodeling following angiotensin II insult. Mice were subjected to angiotensin II infusion to induce a cardiac adverse remodeling model. An adeno-associated virus (AAV) 9 system was used to deliver ZBTB20 to the mouse heart. Here, we demonstrate that ZBTB20 expression is elevated in angiotensin II-induced cardiac remodeling and in response to cardiomyocyte insults. Furthermore, AAV9-mediated overexpression of ZBTB20 caused cardiac wall hypertrophy, chamber dilation, increased fibrosis, and reduced ejection fraction. Additionally, ZBTB20 siRNA protected cardiomyocytes from angiotensin II-induced hypertrophy. Mechanistically, ZBTB20 interferes with EGFR and Akt signaling and modulates the remodeling response. Overexpression of constitutively active Akt counteracts ZBTB20 knockdown-mediated protection of adverse cardiac remodeling. These findings illustrate the role of ZBTB20 in the transition of adverse cardiac remodeling toward heart failure and provide evidence for the molecular programs inducing adverse cardiac remodeling.

Key messages

  • ZBTB20 is a transcription factor from the POK family.

  • ZBTB20 is upregulated in heart tissue treated with angiotensin II.

  • ZBTB20 influences cardiomyocyte hypertrophy via the EGFR-Akt pathway.

  • Akt continuous activation leads to similar results to ZBTB20 overexpression.

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All data will be available upon request from the corresponding author.

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Funding

This research was supported by the National Natural Science Foundation of China (Grant No. 81900216) and the Science and Technology Program of Xuzhou KC18173.

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Authors and Affiliations

  1. Department of Cardiothoracic Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221000, People’s Republic of China

    Fangfang Li, Miaomiao Du, Yiming Yang, Zhu Wang, Hu Zhang, Xiaoyu Wang & Qing Li

  2. Jiangsu Provincial Institute of Health Emergency, Xuzhou Medical University, Xuzhou, 221000, China

    Fangfang Li, Miaomiao Du, Yiming Yang, Zhu Wang, Hu Zhang, Xiaoyu Wang & Qing Li

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  1. Fangfang Li
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  2. Miaomiao Du
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  4. Zhu Wang
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  5. Hu Zhang
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  7. Qing Li
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Contributions

LF and LQ contributed to the study conception and designed the experiments; LF, YM, WZ, and ZH carried out the experiments; WX and DM analyzed the experimental results; and LF, LQ and WZ wrote and revised the manuscript.

Corresponding author

Correspondence to Qing Li.

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Ethics approval

The Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health was applied to all animal procedures in our experiment, and approval from the Institutional Animal Care and Use Committee at Xuzhou Medical University (Xuzhou, China; Approval number: JSXZ-2018–1012-007; Approval data: 12/10/2018) was also acquired.

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Li, F., Du, M., Yang, Y. et al. Zinc finger and BTB domain-containing protein 20 aggravates angiotensin II-induced cardiac remodeling via the EGFR-AKT pathway. J Mol Med 100, 427–438 (2022). https://doi.org/10.1007/s00109-021-02103-0

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  • DOI: https://doi.org/10.1007/s00109-021-02103-0

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