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

Nat Commun. 2024 Sep 12;15(1):7638. doi: 10.1038/s41467-024-52068-0.

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.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Extracellular Matrix / metabolism
  • Fibroblasts* / metabolism
  • Fibroblasts* / pathology
  • Fibrosis*
  • Heart Failure* / genetics
  • Heart Failure* / metabolism
  • Heart Failure* / pathology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium* / metabolism
  • Myocardium* / pathology
  • Myofibroblasts* / metabolism
  • Myofibroblasts* / pathology
  • Phosphorylation
  • Protein Kinase C* / genetics
  • Protein Kinase C* / metabolism
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Protein Kinase C
  • protein kinase N
  • p38 Mitogen-Activated Protein Kinases