{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T03:05:25Z","timestamp":1793415925243,"version":"4.5.0"},"reference-count":58,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","funder":[{"DOI":"10.13039\/501100008530","name":"EC | European Regional Development Fund","doi-asserted-by":"publisher","award":["CZ.02.1.01\/0.0\/0.0\/15_003\/0000492"],"award-info":[{"award-number":["CZ.02.1.01\/0.0\/0.0\/15_003\/0000492"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Portuguese foundation for science and technology","award":["PTDC\/SAU-ORG\/118297\/2010"],"award-info":[{"award-number":["PTDC\/SAU-ORG\/118297\/2010"]}]}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2021,1,8]]},"abstract":"<jats:sec>\n                    <jats:title>Rationale:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives:<\/jats:title>\n                    <jats:p>We aimed to (1) identify consistent modifications to cardiac ECM structure and mechanics that contribute to HF and (2) determine the underlying molecular mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results:<\/jats:title>\n                    <jats:p>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\u03b21 (transforming growth factor \u03b21), interleukin-1, TNF-\u03b1, 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.120.317685","type":"journal-article","created":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T05:01:11Z","timestamp":1603774871000},"page":"24-38","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":124,"title":["Multiscale Analysis of Extracellular Matrix Remodeling in the Failing Heart"],"prefix":"10.1161","volume":"128","author":[{"given":"Ana Rubina","family":"Perestrelo","sequence":"first","affiliation":[{"name":"International Clinical Research Center, St. Anne\u2019s University Hospital Brno, Czech Republic (A.R.P., J.O.-D.L.C., F.M., V.H., G.C., O.P., V.V., S.P., K.K., G.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Catarina","family":"Silva","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade and Instituto Nacional de Engenharia Biom\u00e9dica, Universidade do Porto (A.C.S., P.P.-d.\u00d3., D.S.N.)."},{"name":"Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto, Porto, Portugal (A.C.S., P.P.-d.\u00d3., D.S.N.)."},{"name":"Gladstone Institute University of Cardiovascular Disease, San Francisco (A.C.S., J.O.-D.L.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7536-8067","authenticated-orcid":true,"given":"Jorge","family":"Oliver-De La Cruz","sequence":"additional","affiliation":[{"name":"International Clinical Research Center, St. Anne\u2019s University Hospital Brno, Czech Republic (A.R.P., J.O.-D.L.C., F.M., V.H., G.C., O.P., V.V., S.P., K.K., G.F.)."},{"name":"Gladstone Institute University of Cardiovascular Disease, San Francisco (A.C.S., J.O.-D.L.C.)."},{"name":"Competence Center for Mechanobiology in Regenerative Medicine, INTERREG ATCZ133, Brno, Czech Republic (J.O.-D.L.C., F.M., V.V., G.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"Martino","sequence":"additional","affiliation":[{"name":"International Clinical Research Center, St. Anne\u2019s University Hospital Brno, Czech Republic (A.R.P., J.O.-D.L.C., F.M., V.H., G.C., O.P., V.V., S.P., K.K., G.F.)."},{"name":"Competence Center 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