Abstract 10698: Syndecan-4 Regulates Myofibroblast Differentiation Following Mechanical Stress
Mechanical stress caused by pressure overload of the heart leads to differentiation of cardiac fibroblasts into myofibroblasts characterized by the ability to contract and an excessive production of extracellular matrix. This compromises heart function by increasing stiffness of the myocardium. The molecular mechanisms for stress-induced myofibroblast differentiation are likely to involve stress-sensing molecules located in focal adhesions, such as the transmembrane proteoglycan syndecan-4. We have previously shown that syndecan-4 activates the calcineurin-NFAT (nuclear factor of activated T-cells) signaling system in cardiomyocytes during development of cardiac hypertrophy. However, the role of this signaling pathway in cardiac fibroblasts is not clear. Here, we hypothesized that syndecan-4 activates NFAT in response to mechanical stress leading to myofibroblast differentiation. In vivo, aortic banding caused a 2.2-fold increase of the myofibroblast marker gene smooth muscle α-actin (SMα-actin) in wild type hearts. Strikingly, this effect was completely absent in the syndecan-4 knockout (KO) hearts, indicating an essential role for syndecan-4 in myofibroblast differentiation during pressure overload. Following cyclic stretch (10 %, 1 Hz) of cardiac fibroblasts in vitro, NFATc4 was found to become activated in a calcineurin-dependent manner. This activation was significantly reduced in syndecan-4 KO cardiac fibroblasts implying involvement of syndecan-4 in stretch-induced NFAT activation. Furthermore, syndecan-4 and calcineurin colocalized (proximity ligation assay) suggesting a possible interaction. Previously, we have found that phosphorylation of serine 179 (pS179) in the cytoplasmic part of syndecan-4 negatively regulates binding and activation of calcineurin in cardiomyocytes. Following cyclic stretch of cardiac fibroblasts, pS179 was reduced by 50%, favouring calcineurin-NFAT activation. Finally, overexpressing NFATc4 in fibroblasts caused a 2.3-fold increase in SMα-actin after stretch. In conclusion, we show that syndecan-4 activates calcineurin-NFAT signaling in mechanically stressed cardiac fibroblasts and that this signaling pathway could induce the differentiation into myofibroblasts.
- © 2011 by American Heart Association, Inc.