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      Combined role for YAP-TEAD and YAP-RUNX2 signalling in substrate-stiffness regulation of cardiac fibroblast proliferation.

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          Abstract

          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. Here we characterise a novel mechanism involving a combined activation of Yes-associated protein (YAP) targets RUNX Family Transcription Factor 2 (RUNX2) and TEA Domain Transcription Factor (TEAD). We demonstrate that cardiac fibroblast proliferation is enhanced by interaction with a stiff ECM compared to a soft ECM. This is associated with activation of the transcriptional co-factor, YAP. We demonstrate that this stiffness induced activation of YAP enhances the transcriptional activity of both TEAD and RUNX2 transcription factors. 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.

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          Author and article information

          Journal
          Biochim Biophys Acta Mol Cell Res
          Biochimica et biophysica acta. Molecular cell research
          Elsevier BV
          1879-2596
          0167-4889
          Nov 2022
          : 1869
          : 11
          Affiliations
          [1 ] School of Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Research Floor Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
          [2 ] School of Translational Health Sciences, Faculty of Health Sciences, University of Bristol, Research Floor Level 7, Bristol Royal Infirmary, Bristol BS2 8HW, UK. Electronic address: mark.bond@bris.ac.uk.
          Article
          S0167-4889(22)00121-5
          10.1016/j.bbamcr.2022.119329
          35905788
          139733eb-875e-4f7d-abb1-f609095f771f
          History

          YAP,Cardiac,Fibroblast,Proliferation,RUNX2
          YAP, Cardiac, Fibroblast, Proliferation, RUNX2

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