6533b872fe1ef96bd12d2ed6
RESEARCH PRODUCT
Reduction of Cardiac Fibrosis by Interference With YAP-Dependent Transactivation
Gloria GaroffoloManuel CasaburoFrancesco AmadeoMassimo SalviGiacomo BernavaLuca PiacentiniIsotta ChimentiGermana ZaccagniniGesmi MilcovichEstella ZuccoloMarco AgrifoglioSara RagazziniOtgon BaasansurenClaudia CozzolinoMattia ChiesaSilvia FerrariDario CarbonaroRosaria SantoroMartina ManzoniLoredana CasalisAngela RaucciFilippo MolinariLorenzo MenicantiFrancesca PaganoToshiro OhashiFabio MartelliDiana MassaiGualtiero I. ColomboElisa MessinaUmberto MorbiducciMaurizio Pescesubject
Transcriptional ActivationPhysiologyfibrosismyofibroblastsVerteporfinheart failureYAP-Signaling ProteinsSettore MED/11 - Malattie dell'Apparato CardiovascolareSettore MED/23 - Chirurgia Cardiacafibrosis; heart failure; myofibroblasts; stromal cell; transcription factorsstromal cellPhosphoproteinscell mechanics; fibrosis; heart failure; myofibroblasts; stromal cell; YAP transcription factor;MiceYAP transcription factorcell mechanicsSettore CHIM/09 - Farmaceutico Tecnologico Applicativotranscription factorsTrans-ActivatorsAnimalsHumansCardiology and Cardiovascular MedicineAdaptor Proteins Signal Transducingdescription
Background: Conversion of cardiac stromal cells into myofibroblasts is typically associated with hypoxia conditions, metabolic insults, and/or inflammation, all of which are predisposing factors to cardiac fibrosis and heart failure. We hypothesized that this conversion could be also mediated by response of these cells to mechanical cues through activation of the Hippo transcriptional pathway. The objective of the present study was to assess the role of cellular/nuclear straining forces acting in myofibroblast differentiation of cardiac stromal cells under the control of YAP (yes-associated protein) transcription factor and to validate this finding using a pharmacological agent that interferes with the interactions of the YAP/TAZ (transcriptional coactivator with PDZ-binding motif) complex with their cognate transcription factors TEADs (TEA domain transcription factors), under high-strain and profibrotic stimulation. Methods: We employed high content imaging, 2-dimensional/3-dimensional culture, atomic force microscopy mapping, and molecular methods to prove the role of cell/nuclear straining in YAP-dependent fibrotic programming in a mouse model of ischemia-dependent cardiac fibrosis and in human-derived primitive cardiac stromal cells. We also tested treatment of cells with Verteporfin, a drug known to prevent the association of the YAP/TAZ complex with their cognate transcription factors TEADs. Results: Our experiments suggested that pharmacologically targeting the YAP-dependent pathway overrides the profibrotic activation of cardiac stromal cells by mechanical cues in vitro, and that this occurs even in the presence of profibrotic signaling mediated by TGF-β1 (transforming growth factor beta-1). In vivo administration of Verteporfin in mice with permanent cardiac ischemia reduced significantly fibrosis and morphometric remodeling but did not improve cardiac performance. Conclusions: Our study indicates that preventing molecular translation of mechanical cues in cardiac stromal cells reduces the impact of cardiac maladaptive remodeling with a positive effect on fibrosis.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2022-07-22 |