J 2021

Multiscale Analysis of Extracellular Matrix Remodeling in the Failing Heart

PERESTRELO, A. R., A. C. SILVA, J. OLIVER-DE LA CRUZ, Fabiana MARTINO, Vladimir HORVATH et. al.

Basic information

Original name

Multiscale Analysis of Extracellular Matrix Remodeling in the Failing Heart

Authors

PERESTRELO, A. R. (guarantor), A. C. SILVA, J. OLIVER-DE LA CRUZ, Fabiana MARTINO (380 Italy, belonging to the institution), Vladimir HORVATH (203 Czech Republic), Guido CALUORI (380 Italy, belonging to the institution), Ondrej POLANSKY (203 Czech Republic), Vladimir VINARSKY (203 Czech Republic), G. AZZATO, G. DE MARCO, Víta ŽAMPACHOVÁ (203 Czech Republic, belonging to the institution), Petr SKLÁDAL (203 Czech Republic, belonging to the institution), S. PAGLIARI, A. RAINER, P. PINTO-DO-O, A. CARAVELLA, Kamila KOCI (203 Czech Republic), D. S. NASCIMENTO and Giancarlo FORTE (380 Italy)

Edition

Circulation research, Dallas, American Heart Association, 2021, 0009-7330

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30201 Cardiac and Cardiovascular systems

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

Impact factor

Impact factor: 23.213

RIV identification code

RIV/00216224:14110/21:00123975

Organization unit

Faculty of Medicine

UT WoS

000639316500005

Keywords in English

cardiomyopathy; dilated; elasticity; extracellular matrix; fibroblasts

Tags

International impact, Reviewed
Změněno: 17/5/2022 12:59, Mgr. Tereza Miškechová

Abstract

V originále

Rationale: Cardiac ECM (extracellular matrix) comprises a dynamic molecular network providing structural support to heart tissue function. Understanding the impact of ECM remodeling on cardiac cells during heart failure (HF) is essential to prevent adverse ventricular remodeling and restore organ functionality in affected patients. Objectives: We aimed to (1) identify consistent modifications to cardiac ECM structure and mechanics that contribute to HF and (2) determine the underlying molecular mechanisms. Methods and Results: We first performed decellularization of human and murine ECM (decellularized ECM) and then analyzed the pathological changes occurring in decellularized ECM during HF by atomic force microscopy, 2-photon microscopy, high-resolution 3-dimensional image analysis, and computational fluid dynamics simulation. We then performed molecular and functional assays in patient-derived cardiac fibroblasts based on YAP (yes-associated protein)-transcriptional enhanced associate domain (TEAD) mechanosensing activity and collagen contraction assays. The analysis of HF decellularized ECM resulting from ischemic or dilated cardiomyopathy, as well as from mouse infarcted tissue, identified a common pattern of modifications in their 3-dimensional topography. As compared with healthy heart, HF ECM exhibited aligned, flat, and compact fiber bundles, with reduced elasticity and organizational complexity. At the molecular level, RNA sequencing of HF cardiac fibroblasts highlighted the overrepresentation of dysregulated genes involved in ECM organization, or being connected to TGF beta 1 (transforming growth factor beta 1), interleukin-1, TNF-alpha, and BDNF signaling pathways. Functional tests performed on HF cardiac fibroblasts pointed at mechanosensor YAP as a key player in ECM remodeling in the diseased heart via transcriptional activation of focal adhesion assembly. Finally, in vitro experiments clarified pathological cardiac ECM prevents cell homing, thus providing further hints to identify a possible window of action for cell therapy in cardiac diseases. Conclusions: Our multiparametric approach has highlighted repercussions of ECM remodeling on cell homing, cardiac fibroblast activation, and focal adhesion protein expression via hyperactivated YAP signaling during HF.

Links

LM2018127, research and development project
Name: Česká infrastruktura pro integrativní strukturní biologii (Acronym: CIISB)
Investor: Ministry of Education, Youth and Sports of the CR