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Protein kinase N promotes cardiac fibrosis in heart failure by fibroblast-to-myofibroblast conversion

Author

Listed:
  • Satoya Yoshida

    (Nagoya University School of Medicine)

  • Tatsuya Yoshida

    (Nagoya University School of Medicine)

  • Kohei Inukai

    (Nagoya University School of Medicine)

  • Katsuhiro Kato

    (Nagoya University School of Medicine)

  • Yoshimitsu Yura

    (Nagoya University School of Medicine)

  • Tomoki Hattori

    (Nagoya University School of Medicine)

  • Atsushi Enomoto

    (Nagoya University School of Medicine)

  • Koji Ohashi

    (Nagoya University School of Medicine)

  • Takahiro Okumura

    (Nagoya University School of Medicine)

  • Noriyuki Ouchi

    (Nagoya University School of Medicine)

  • Haruya Kawase

    (Nagoya University School of Medicine
    Max Planck Institute for Heart and Lung Research)

  • Nina Wettschureck

    (Max Planck Institute for Heart and Lung Research)

  • Stefan Offermanns

    (Max Planck Institute for Heart and Lung Research)

  • Toyoaki Murohara

    (Nagoya University School of Medicine)

  • Mikito Takefuji

    (Nagoya University School of Medicine)

Abstract

Chronic fibrotic tissue disrupts various organ functions. Despite significant advances in therapies, mortality and morbidity due to heart failure remain high, resulting in poor quality of life. Beyond the cardiomyocyte-centric view of heart failure, it is now accepted that alterations in the interstitial extracellular matrix (ECM) also play a major role in the development of heart failure. Here, we show that protein kinase N (PKN) is expressed in cardiac fibroblasts. Furthermore, PKN mediates the conversion of fibroblasts into myofibroblasts, which plays a central role in secreting large amounts of ECM proteins via p38 phosphorylation signaling. Fibroblast-specific deletion of PKN led to a reduction of myocardial fibrotic changes and cardiac dysfunction in mice models of ischemia-reperfusion or heart failure with preserved ejection fraction. Our results indicate that PKN is a therapeutic target for cardiac fibrosis in heart failure.

Suggested Citation

  • Satoya Yoshida & Tatsuya Yoshida & Kohei Inukai & Katsuhiro Kato & Yoshimitsu Yura & Tomoki Hattori & Atsushi Enomoto & Koji Ohashi & Takahiro Okumura & Noriyuki Ouchi & Haruya Kawase & Nina Wettschur, 2024. "Protein kinase N promotes cardiac fibrosis in heart failure by fibroblast-to-myofibroblast conversion," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52068-0
    DOI: 10.1038/s41467-024-52068-0
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    References listed on IDEAS

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    1. Gabriele G. Schiattarella & Francisco Altamirano & Dan Tong & Kristin M. French & Elisa Villalobos & Soo Young Kim & Xiang Luo & Nan Jiang & Herman I. May & Zhao V. Wang & Theodore M. Hill & Pradeep P, 2019. "Nitrosative stress drives heart failure with preserved ejection fraction," Nature, Nature, vol. 568(7752), pages 351-356, April.
    2. Lufen Chang & Michael Karin, 2001. "Mammalian MAP kinase signalling cascades," Nature, Nature, vol. 410(6824), pages 37-40, March.
    3. Neil C. Henderson & Florian Rieder & Thomas A. Wynn, 2020. "Fibrosis: from mechanisms to medicines," Nature, Nature, vol. 587(7835), pages 555-566, November.
    4. Kazumasa Kanemaru & James Cranley & Daniele Muraro & Antonio M. A. Miranda & Siew Yen Ho & Anna Wilbrey-Clark & Jan Patrick Pett & Krzysztof Polanski & Laura Richardson & Monika Litvinukova & Natsuhik, 2023. "Spatially resolved multiomics of human cardiac niches," Nature, Nature, vol. 619(7971), pages 801-810, July.
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