Article Impact Level: HIGH Data Quality: STRONG Summary of Nature Communications, 15(1), 7638. https://doi.org/10.1038/s41467-024-52068-0 Dr. Satoya Yoshida et al.
Points
- Protein kinase N (PKN) plays a crucial role in cardiac fibrosis by promoting the conversion of cardiac fibroblasts into myofibroblasts, which are responsible for excessive extracellular matrix (ECM) deposition.
- PKN facilitates this process through p38 phosphorylation signaling, contributing to heart tissue stiffening and worsening heart function in heart failure.
- Mouse models of ischemic heart failure and heart failure with preserved ejection fraction (HFpEF) showed that fibroblast-specific deletion of PKN reduced myocardial fibrosis and improved heart function.
- PKN activates fibroblasts via the RHOA signaling pathway, leading to ECM buildup. Mice lacking PKN in fibroblasts exhibited significantly less fibrosis and better heart function.
- The study suggests that PKN could be a novel therapeutic target for reducing cardiac fibrosis and slowing the progression of heart failure by inhibiting fibroblast activity.
Summary
This study investigates the role of protein kinase N (PKN) in cardiac fibrosis, a critical factor contributing to heart failure progression. Cardiac fibrosis, characterized by excessive extracellular matrix (ECM) deposition, leads to stiffening of the heart tissue and worsens heart function. The researchers identified that PKN is expressed in cardiac fibroblasts and facilitates the conversion of these cells into myofibroblasts, which are responsible for secreting large amounts of ECM proteins. This process is mediated via p38 phosphorylation signaling. The study used mouse models of ischemia-reperfusion and heart failure with preserved ejection fraction (HFpEF), demonstrating that fibroblast-specific deletion of PKN reduced myocardial fibrosis and improved heart function. These findings suggest that PKN could be a novel therapeutic target for cardiac fibrosis in heart failure.
The study builds on the understanding that, beyond cardiomyocytes, changes in the cardiac ECM play a central role in heart failure. Cardiac fibrosis is involved in common conditions like myocardial infarction, which leads to scar formation and impaired heart function. Chronic fibrosis, especially in areas remote from the infarcted region, increases ventricular stiffness and reduces cardiac output. The researchers demonstrated that inhibition of PKN in fibroblasts significantly mitigated fibrotic changes and improved heart function, highlighting the importance of targeting fibroblast activity in managing heart failure. This reduction in fibrosis was observed in models of both ischemic heart failure and HFpEF, conditions known for their high fibrosis burden.
The experimental results showed that PKN activates fibroblasts via the RHOA signaling pathway, promoting ECM deposition and strengthening heart tissue. Mice lacking PKN in fibroblasts had significantly reduced cardiac fibrosis and improved heart function compared to controls. These results highlight the therapeutic potential of PKN inhibition, which could reduce the progression of heart failure by limiting fibrosis. This study paves the way for further research into targeted treatments to modulate fibroblast activity to manage or prevent heart failure.
Link to the article: https://www.nature.com/articles/s41467-024-52068-0
References Yoshida, S., Yoshida, T., Inukai, K., Kato, K., Yura, Y., Hattori, T., Enomoto, A., Ohashi, K., Okumura, T., Ouchi, N., Kawase, H., Wettschureck, N., Offermanns, S., Murohara, T., & Takefuji, M. (2024). Protein kinase N promotes cardiac fibrosis in heart failure by fibroblast-to-myofibroblast conversion. Nature Communications, 15(1), 7638. https://doi.org/10.1038/s41467-024-52068-0
