Journal article
Extracellular matrix stiffness controls cardiac valve myofibroblast activation through epigenetic remodeling
Bioengineering & translational medicine, Vol.7(3), pp.e10394-n/a
08/22/2022
DOI: 10.1002/btm2.10394
PMCID: PMC9472021
PMID: 36176599
Abstract
Aortic valve stenosis (AVS) is a progressive fibrotic disease that is caused by thickening and stiffening of valve leaflets. At the cellular level, quiescent valve interstitial cells (qVICs) activate to myofibroblasts (aVICs) that persist within the valve tissue. Given the persistence of myofibroblasts in AVS, epigenetic mechanisms have been implicated. Here, we studied changes that occur in VICs during myofibroblast activation by using a hydrogel matrix to recapitulate different stiffnesses in the valve leaflet during fibrosis. We first compared the chromatin landscape of qVICs cultured on soft hydrogels and aVICs cultured on stiff hydrogels, representing the native and diseased phenotypes respectively. Using assay for transposase‐accessible chromatin sequencing (ATAC‐Seq), we found that open chromatin regions in aVICs were enriched for transcription factor binding motifs associated with mechanosensing pathways compared to qVICs. Next, we used RNA‐Seq to show that the open chromatin regions in aVICs correlated with pro‐fibrotic gene expression, as aVICs expressed higher levels of contractile fiber genes, including myofibroblast markers such as alpha smooth muscle actin (αSMA), compared to qVICs. In contrast, chromatin remodeling genes were downregulated in aVICs compared to qVICs, indicating qVICs may be protected from myofibroblast activation through epigenetic mechanisms. Small molecule inhibition of one of these remodelers, CREB Binding Protein (CREBBP), prevented qVICs from activating to aVICs. Notably, CREBBP is more abundant in valves from healthy patients compared to fibrotic valves. Our findings reveal the role of mechanical regulation in chromatin remodeling during VIC activation and quiescence and highlight one potential therapeutic target for treating AVS.
Details
- Title: Subtitle
- Extracellular matrix stiffness controls cardiac valve myofibroblast activation through epigenetic remodeling
- Creators
- Cierra J. Walker - University of Colorado BoulderDilara Batan - University of Colorado BoulderCarrie T. Bishop - University of Colorado BoulderDaniel Ramirez - University of Colorado BoulderBrian A. Aguado - University of Colorado BoulderMegan E. Schroeder - University of Colorado BoulderClaudia Crocini - University of Colorado BoulderJessica Schwisow - University of Colorado Anschutz Medical CampusKaren Moulton - University of Colorado Anschutz Medical CampusLaura Macdougall - University of Colorado BoulderRobert M. Weiss - University of IowaMary A. Allen - University of Colorado BoulderRobin Dowell - University of Colorado BoulderLeslie A. Leinwand - University of Colorado BoulderKristi S. Anseth - University of Colorado Boulder
- Resource Type
- Journal article
- Publication Details
- Bioengineering & translational medicine, Vol.7(3), pp.e10394-n/a
- DOI
- 10.1002/btm2.10394
- PMID
- 36176599
- PMCID
- PMC9472021
- NLM abbreviation
- Bioeng Transl Med
- ISSN
- 2380-6761
- eISSN
- 2380-6761
- Publisher
- John Wiley & Sons, Inc
- Grant note
- ; FHL142223; K99 HL148542; R01 GM29090; R01HL132353; R01HL142935; RHL117138‐05; RO1 GM125871; T32 HL007822 / ; LT001449/2017‐L / Human Frontiers Science Program fellowship University of Colorado BSI Scholars 1S10OD012300 / ; 20POST3521111; 20PRE35200068 / ; W911NF‐19‐2‐0024 / ;
- Alternative title
- Walker et al
- Language
- English
- Date published
- 08/22/2022
- Academic Unit
- Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984359852002771
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