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BS44 Combined role for yap-tead and YAP-RUNX2 signalling in substrate stiffness regulation of cardiac fibroblast proliferation
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BS44 Combined role for yap-tead and YAP-RUNX2 signalling in substrate stiffness regulation of cardiac fibroblast proliferation
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Journal Article
BS44 Combined role for yap-tead and YAP-RUNX2 signalling in substrate stiffness regulation of cardiac fibroblast proliferation
2022
Overview
Cardiac fibrosis is associated with increased stiffness of the myocardial extracellular matrix (ECM) in part mediated by increased cardiac fibroblast proliferation However, our understanding of the mechanisms regulating cardiac fibroblast proliferation are incomplete. Cardiac fibrosis is associated with increased stiffness of the myocardial extracellular matrix (ECM). Here we characterise a novel mechanism involving a combined activation of YAP targets RUNX Family Transcription Factor 2 (RUNX2) and TEA Domain Transcription Factor (TEAD). Using collagen-coated polyacrylamide hydrogels of tuneable stiffness, we demonstrate that cardiac fibroblast proliferation, quantified using Edu incorporation, is enhanced by interaction with a stiff (50 kPa) ECM compared to a soft (0.5 kPa) ECM (7.02±0.77% on soft vs 33.10±0.52% on stiff; p<0.01). This is associated with activation of the transcriptional co-factor, YAP, indicated by reduced phosphorylation and increased nuclear localisation in cells cultured on stiff substrates. Reporter gene assays demonstrate that stiffness induced activation of YAP significantly enhances the transcriptional activity of both TEAD and RUNX2 transcription factors. Overexpression of an activate YAP mutant significantly enhanced TEAD and RUNX2 activity, whereas YAP silencing significantly reduced TEAD and RUNX2 activity. Inhibition of either TEAD or RUNX2, using gene silencing, expression of dominant-negative mutants or pharmacological inhibition, reduces cardiac fibroblast proliferation. Using mutants of YAP, defective in TEAD or RUNX2 activation ability, we demonstrate a dual role of YAP-mediated activation of TEAD and RUNX2 for substrate stiffness induced cardiac fibroblast proliferation. Our data highlights a previously unrecognised role of YAP mediated RUNX2 activation for cardiac fibroblast proliferation in response to increased ECM stiffness.
Publisher
BMJ Publishing Group Ltd and British Cardiovascular Society,BMJ Publishing Group LTD
Subject
