Mechanical Stress activates NFATc4 in Cardiac Fibroblasts via Syndecan‐4

Abstract

Cardiac fibroblasts differentiate into myofibroblasts in response to left ventricular pressure overload. Myofibroblasts have contractile properties and produce excessive amounts of extracellular matrix, thereby increasing myocardial stiffness. The objective of this study was to investigate the role of the focal adhesion transmembrane protein syndecan‐4 as a stress‐sensor activating nuclear factor of activated T‐cells (NFAT) and thereby inducing myofibroblast differentiation. Aortic banding increased mRNA levels of the myofibroblast marker gene smooth muscle α‐actin, as well as collagen I and III in wild‐type left ventricles but not in the syndecan‐4 knockout (KO) hearts. Stretch caused translocation of GFP‐NFATc4 fusion proteins to the nucleus indicating activation of this isoform. Furthermore, NFATc4 was dephosphorylated (activated) following stretch in a calcineurin‐and syndecan‐4‐dependent manner. Finally, overexpressing NFATc4 caused an increase in the myofibroblast‐associated myocardin‐related transcription factor A. In conclusion, we show that syndecan‐4 activates NFATc4 signaling following stretch and this may cause myofibroblast differentiation.Source of research support: Norwegian Health Association