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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.
