Multiscale Analysis of Extracellular Matrix Remodeling in the Failing Heart.

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00209775%3A_____%2F22%3AN0000024" target="_blank" >RIV/00209775:_____/22:N0000024 - isvavai.cz</a>

Alternative codes found

RIV/00159816:_____/21:00075159 RIV/00216224:14110/21:00123975

Result on the web

<a href="https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.120.317685?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org#d1e522" target="_blank" >https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.120.317685?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org#d1e522</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1161/CIRCRESAHA.120.317685" target="_blank" >10.1161/CIRCRESAHA.120.317685</a>

Result language

angličtina

Original language name

Multiscale Analysis of Extracellular Matrix Remodeling in the Failing Heart.

Original language description

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 TGFβ1 (transforming growth factor β1), interleukin-1, TNF-α, 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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30201 - Cardiac and Cardiovascular systems

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2022

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Circulation Research

ISSN

0009-7330

e-ISSN

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Volume of the periodical

128

Issue of the periodical within the volume

1

Country of publishing house

US - UNITED STATES

Number of pages

5

Pages from-to

24-38

UT code for WoS article

000639316500005

EID of the result in the Scopus database

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