Acta Physiologica 2011; Volume 202, Supplement 685
Scandinavian Physiological Society's Annual Meeting
SYNDECAN-4 REGULATES NFAT ACTIVATION IN CARDIAC FIBROBLASTS FOLLOWING STRETCH
Abstract number: 8.1.1
HERUM1 KLM, LUNDE1 IG, BEHMEN1 D, FLORHOLMEN1 G, CARLSON1 CR, CHRISTENSEN1 GA
1Institute for Experimental Medical Research, Oslo University Hospital Ullevl, Kirkeveien 166, 0407 Oslo, Norway; Email: firstname.lastname@example.org
Cardiac fibroblasts respond to stretch by differentiating into myofibroblasts that have contractile properties and produce large amounts of extracellular matrix. This may cause fibrosis and hence cardiac dysfunction. The mechanisms triggering this response are unknown. Here, we investigated whether syndecan-4 is a stretch sensor in cardiac fibroblasts which activates calcineurin-NFAT (nuclear factor of activated T-cells) signaling that may be involved in stretch-induced fibroblast to myofibroblast differentiation.
Cardiac fibroblasts from wild type and syndecan-4 knockout mice were isolated and plated on collagen I-coated silicon membranes and then subjected to cyclic stretch (10%, 24 hrs, 1 Hz). Colocalization was determined with proximity ligation assay and overexpression of syndecan-4 was done in HT1080 fibroblasts.
NFATc4 was dephosphorylated (activated) in response to stretch. This activation was abolished in the presence of the calcineurin inhibitor cyclosporine A and significantly reduced in cardiac fibroblasts from syndecan-4 knockout mice. Colocalization of syndecan-4 and calcineurin implied interaction between these two proteins and previous studies in cardiomyocytes have identified a direct binding between calcineurin and the cytosolic region of syndecan-4. Phosphorylation of ser179 in this region was reduced by 50% in cardiac fibroblasts subjected to mechanical stress and could therefore be involved in the regulation of calcineurin-NFAT signaling in response to stretch.
Stretch activated NFATc4 in a syndecan-4-dependent manner. The mechanism for this activation is likely to involve intracellular dephosphorylation of syndecan-4 thereby enabling calcineurin-NFAT signaling. This pathway may be important for the differentiation of cardiac fibroblasts to myofibroblasts following stretch.
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Acta Physiologica 2011; Volume 202, Supplement 685 :8.1.1