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Dusp6 deficiency attenuates neutrophil-mediated cardiac damage in the acute inflammatory phase of myocardial infarction

Author

Listed:
  • Xiaohai Zhou

    (Peking University)

  • Chenyang Zhang

    (Peking University
    PKU-Nanjing Institute of Translational Medicine)

  • Xueying Wu

    (Peking University)

  • Xinli Hu

    (Peking University)

  • Yan Zhang

    (Peking University)

  • Xuelian Wang

    (Peking University)

  • Lixia Zheng

    (Peking University)

  • Peng Gao

    (Peking University)

  • Jianyong Du

    (Peking University)

  • Wen Zheng

    (Peking University)

  • Haibao Shang

    (Peking University)

  • Keping Hu

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Zhengfan Jiang

    (Peking University)

  • Yu Nie

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Shengshou Hu

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Rui-Ping Xiao

    (Peking University
    PKU-Nanjing Institute of Translational Medicine)

  • Xiaojun Zhu

    (Peking University
    PKU-Nanjing Institute of Translational Medicine)

  • Jing-Wei Xiong

    (Peking University
    PKU-Nanjing Institute of Translational Medicine)

Abstract

Dual-specificity phosphatase 6 (DUSP6) serves a specific and conserved function on the dephosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). We previously identified Dusp6 as a regenerative repressor during zebrafish heart regeneration, therefore we propose to investigate the role of this repressor in mammalian cardiac repair. Utilizing a rat strain harboring Dusp6 nonsense mutation, rat neutrophil-cardiomyocyte co-culture, bone marrow transplanted rats and neutrophil-specific Dusp6 knockout mice, we find that Dusp6 deficiency improves cardiac outcomes by predominantly attenuating neutrophil-mediated myocardial damage in acute inflammatory phase after myocardial infarction. Mechanistically, Dusp6 is transcriptionally activated by p38-C/EBPβ signaling and acts as an effector for maintaining p-p38 activity by down-regulating pERK and p38-targeting phosphatases DUSP1/DUSP16. Our findings provide robust animal models and novel insights for neutrophil-mediated cardiac damage and demonstrate the potential of DUSP6 as a therapeutic target for post-MI cardiac remodeling and other relevant inflammatory diseases.

Suggested Citation

  • Xiaohai Zhou & Chenyang Zhang & Xueying Wu & Xinli Hu & Yan Zhang & Xuelian Wang & Lixia Zheng & Peng Gao & Jianyong Du & Wen Zheng & Haibao Shang & Keping Hu & Zhengfan Jiang & Yu Nie & Shengshou Hu , 2022. "Dusp6 deficiency attenuates neutrophil-mediated cardiac damage in the acute inflammatory phase of myocardial infarction," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33631-z
    DOI: 10.1038/s41467-022-33631-z
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    References listed on IDEAS

    as
    1. Ahmed I. Mahmoud & Fatih Kocabas & Shalini A. Muralidhar & Wataru Kimura & Ahmed S. Koura & Suwannee Thet & Enzo R. Porrello & Hesham A. Sadek, 2013. "Meis1 regulates postnatal cardiomyocyte cell cycle arrest," Nature, Nature, vol. 497(7448), pages 249-253, May.
    2. Chenglu Xiao & Lu Gao & Yu Hou & Congfei Xu & Nannan Chang & Fang Wang & Keping Hu & Aibin He & Ying Luo & Jun Wang & Jinrong Peng & Fuchou Tang & Xiaojun Zhu & Jing-Wei Xiong, 2016. "Chromatin-remodelling factor Brg1 regulates myocardial proliferation and regeneration in zebrafish," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    3. Eric Ubil & Jinzhu Duan & Indulekha C. L. Pillai & Manuel Rosa-Garrido & Yong Wu & Francesca Bargiacchi & Yan Lu & Seta Stanbouly & Jie Huang & Mauricio Rojas & Thomas M. Vondriska & Enrico Stefani & , 2014. "Mesenchymal–endothelial transition contributes to cardiac neovascularization," Nature, Nature, vol. 514(7524), pages 585-590, October.
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