Centro Cardiologico Monzino IRCCS
Published February 27, 2023 | Version v1
Dataset Restricted

Dataset related to the article "Reduction of Cardiac Fibrosis by Interference With YAP-Dependent Transactivation"

Authors/Creators

  • 1. Centro Cardiologico Monzino
  • 2. politecnico di Torino
  • 3. Sapienza University of Rome
  • 4. Policlinico San Donato
  • 5. Elettra Sincrotrone ScPA
  • 6. Università di Milano
  • 7. Hokkaido University
  • 8. Politecnico di Torino
  • 9. National Council of Research (IBBC-CNR)
  • 10. Policlinico Umberto I

Description

This record contains raw data related to the article "Reduction of Cardiac Fibrosis by Interference With YAP-Dependent Transactivation".

Abstract

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.

Notes

by RG11916B85CDBF76 granted from Sapienza University to I. Chimenti; by Ricerca Finalizzata RF-12368521 to F. Martelli. F. Martelli is also supported by Telethon-Italy (No. GGP19035), AFM-Téléthon (No. 23054) and the EU-CardioRNA COST Action CA17129.

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Additional details

Related works

Is supplement to
Journal article: 10.1161/CIRCRESAHA.121.319373 (DOI)

Funding

European Commission
COVIRNA - A diagnostic test to improve surveillance and care of COVID-19 patients 101016072
European Commission
MEDIRAD - Implications of Medical Low Dose Radiation Exposure 755523