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Morphological, electrophysiological, and molecular alterations in foetal noncompacted cardiomyopathy induced by disruption of ROCK signalling
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SYSNO ASEP 0599972 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Morphological, electrophysiological, and molecular alterations in foetal noncompacted cardiomyopathy induced by disruption of ROCK signalling Author(s) Sedmera, David (FGU-C) RID, ORCID, SAI
Olejníčková, V. (CZ)
Šaňková, B. (CZ)
Kolesová, H. (CZ)
Bartoš, M. (CZ)
Kvasilová, A. (CZ)
Phillips, L. C. (GB)
Bamforth, S. D. (GB)
Phillips, H. M. (GB)Article number 1471751 Source Title Frontiers in Cell and Developmental Biology. - : Frontiers Research Foundation - ISSN 2296-634X
Roč. 12, 7 Oct (2024)Number of pages 18 s. Language eng - English Country CH - Switzerland Keywords mouse embryonic heart ; ventricular wall ; myocardial trabeculae ; compaction ; conduction ; cardiomyocyte proliferation ; ROCK OECD category Cardiac and Cardiovascular systems R&D Projects GA18-03461S GA ČR - Czech Science Foundation (CSF) LTC17023 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LX22NPO5104 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Research Infrastructure Czech-BioImaging III - 90250 - Ústav molekulární genetiky AV ČR, v. v. i. Method of publishing Open access Institutional support FGU-C - RVO:67985823 UT WOS 001337109700001 EID SCOPUS 85206990280 DOI https://doi.org/10.3389/fcell.2024.1471751 Annotation Left ventricular noncompaction cardiomyopathy is associated with heart failure, arrhythmia, and sudden cardiac death. The developmental mechanism underpinning noncompaction in the adult heart is still not fully understood, with lack of trabeculae compaction, hypertrabeculation, and loss of proliferation cited as possible causes. To study this, we utilised a mouse model of aberrant Rho kinase (ROCK) signalling in cardiomyocytes, which led to a noncompaction phenotype during embryogenesis, and monitored how this progressed after birth and into adulthood. The cause of the early noncompaction at E15.5 was attributed to a decrease in proliferation in the developing ventricular wall. By E18.5, the phenotype became patchy, with regions of noncompaction interspersed with thick compacted areas of ventricular wall. To study how this altered myoarchitecture of the heart influenced impulse propagation in the developing and adult heart, we used histology with immunohistochemistry for gap junction protein expression, optical mapping, and electrocardiography. At the prenatal stages, a clear reduction in left ventricular wall thickness, accompanied by abnormal conduction of the ectopically paced beat in that area, was observed in mutant hearts. This correlated with increased expression of connexin-40 and connexin-43 in noncompacted trabeculae. In postnatal stages, left ventricular noncompaction was resolved, but the right ventricular wall remained structurally abnormal through to adulthood with cardiomyocyte hypertrophy and retention of myocardial crypts. Thus, this is a novel model of self-correcting embryonic hypertrabeculation cardiomyopathy, but it highlights that remodelling potential differs between the left and right ventricles. We conclude that disruption of ROCK signalling induces both morphological and electrophysiological changes that evolve over time, highlighting the link between myocyte proliferation and noncompaction phenotypes and electrophysiological differentiation. Workplace Institute of Physiology Contact Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Year of Publishing 2025 Electronic address https://doi.org/10.3389/fcell.2024.1471751
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