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

Satoya Yoshida, Tatsuya Yoshida, Kohei Inukai, Katsuhiro Kato, Yoshimitsu Yura, Tomoki Hattori, Atsushi Enomoto, Koji Ohashi, Takahiro Okumura, Noriyuki Ouchi, Haruya Kawase, Nina Wettschureck, Stefan Offermanns, Toyoaki Murohara and Mikito Takefuji ()
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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
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

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52068-0

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