Department of Cardiology, Nagoya University School of Medicine, Nagoya, Japan.
Department of Pathology, Nagoya University School of Medicine, Nagoya, Japan.
Nat Commun. 2024 Sep 12;15(1):7638. doi: 10.1038/s41467-024-52068-0.
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.
慢性纤维组织破坏各种器官功能。尽管治疗方法有了显著进展，但心力衰竭导致的死亡率和发病率仍然很高，生活质量较差。除了以心肌细胞为中心的心力衰竭观点外，现在人们已经接受，细胞外基质（ECM）间质的改变也在心力衰竭的发展中起主要作用。在这里，我们表明蛋白激酶 N（PKN）在心脏成纤维细胞中表达。此外，PKN 介导成纤维细胞转化为肌成纤维细胞，通过 p38 磷酸化信号转导在大量 ECM 蛋白的分泌中起核心作用。在缺血再灌注或射血分数保留性心力衰竭的小鼠模型中，特异性敲除成纤维细胞中的 PKN 可减少心肌纤维化改变和心功能障碍。我们的结果表明，PKN 是心力衰竭中心脏纤维化的治疗靶点。
