Abstract 11583: Syndecan-4 Regulates Cardiac Myofibroblast Differentiation and Extracellular Matrix Production in Response to Mechanical Stress by Signaling via NFAT
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 poorly defined but are likely to involve stress-sensing molecules located in focal adhesions, such as the transmembrane proteoglycan syndecan-4. We hypothesized that syndecan-4 responds to mechanical stress by signaling via calcineurin/NFAT to induce myofibroblast differentiation and extracellular matrix production. Aortic banding increased smooth muscle α-actin (SMA; 2-fold), collagen I and III (6-fold) in the left ventricle of WT mice. Remarkably, this response was completely absent in syndecan-4-/- mice, indicating an essential role for syndecan-4 in myofibroblast differentiation in the pressure-overloaded heart. Myofibroblast differentiation as well as NFAT activity was impaired in vitro in cardiac fibroblasts lacking syndecan-4-/-, as assessed by expression of SMA, collagen I and III, and NFAT-luciferase reporter gene expression. Treatment with calcineurin/NFAT blockers inhibited all these responses in fibroblasts from WT mice. Following cyclic stretch, NFATc4 was activated in cardiac fibroblasts in a syndecan-4- and calcineurin-dependent manner and over-expression of syndecan-4 caused dephosphorylation (activation) of NFATc4. Syndecan-4, calcineurin and EGFP-NFATc4 all coincided at focal adhesions, substantiating formation of a mechanosensitive signaling complex. This complex is possibly activated by the 44% reduction in phosphorylated serine179 of syndecan-4 observed after mechanical stress which has previously been found to favor calcineurin interaction. Finally, over-expression of NFATc4 up-regulated collagen III, MRTF-A (a transcriptional regulator of SMA) and the NFAT-target RCAN1.4. In conclusion, we demonstrate that syndecan-4 regulates the production of collagen I and III, and differentiation of cardiac fibroblasts into myofibroblasts in response to mechanical stress in vivo and in vitro by engaging the calcineurin/NFAT signaling pathway.
- © 2012 by American Heart Association, Inc.