Cardiac fibrosis, the excessive accumulation of extracellular matrix (ECM), remains an unresolved problem in most forms of heart disease. In order to be successful in preventing, attenuating or reversing cardiac fibrosis, it is essential to understand the processes leading to ECM production and accumulation. Cardiac fibroblasts are the main producers of cardiac ECM, and harbor great phenotypic plasticity. They are activated by the disease-associated changes in mechanical properties of the heart, including stretch and increased tissue stiffness. Despite much remaining unknown, an interesting body of evidence exists on how mechanical forces are translated into transcriptional responses important for determination of fibroblast phenotype and production of ECM constituents. Such mechanotransduction can occur at multiple cellular locations including the plasma membrane, cytoskeleton and nucleus. Moreover, the ECM functions as a reservoir of pro-fibrotic signaling molecules that can be released upon mechanical stress. We here review the current status of knowledge of mechanotransduction signaling pathways in cardiac fibroblasts that culminate in pro-fibrotic gene expression.

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