Extracellular matrix stiffness induced pro-fibrotic epigenetic remodeling and myofibroblast activation in valve interstitial cells, which was prevented by small molecule inhibition of CREBBP.
Does CREBBP inhibition prevent valve interstitial cell activation to myofibroblasts in a model of aortic valve stenosis?
Mechanical regulation of chromatin remodeling plays a key role in valve interstitial cell activation, and targeting epigenetic remodelers like CREBBP may offer a therapeutic strategy for aortic valve stenosis.
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.
Walker et al. (Fri,) conducted a other in Aortic valve stenosis. Hydrogel matrix stiffness and CREBBP inhibition vs. Soft hydrogels was evaluated on Myofibroblast activation and chromatin remodeling. Extracellular matrix stiffness induced pro-fibrotic epigenetic remodeling and myofibroblast activation in valve interstitial cells, which was prevented by small molecule inhibition of CREBBP.
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