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dc.contributor.author | García Quintáns, Nieves | |
dc.contributor.author | Sacristán, Silvia | |
dc.contributor.author | Márquez López, Cristina | |
dc.contributor.author | Sánchez Ramos, Cristina | |
dc.contributor.author | Martínez de Benito, Fernando | |
dc.contributor.author | Siniscalco, David | |
dc.contributor.author | González Guerra, Andrés | |
dc.contributor.author | Camafeita, Emilio | |
dc.contributor.author | Sanz Rosa, David![]() |
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dc.contributor.author | Bernal, Juan Antonio | |
dc.contributor.author | Et al. | |
dc.date.accessioned | 2023-11-02T11:48:23Z | |
dc.date.available | 2023-11-02T11:48:23Z | |
dc.date.issued | 2023 | |
dc.identifier.citation | García-Quintáns, N., Sacristán, S., Márquez-López, C., Sánchez-Ramos, C., Martínez-de-Benito, F., Siniscalco, D., González-Guerra, A., Camafeita, E., Roche-Molina, M., Lytvyn, M., Morera, D., Guillén, M. I., Sanguino, M. A., Sanz-Rosa, D., Martín-Pérez, D., García, R., & Bernal, J. A. (2023). MYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (Acm). Nature Communications, 14(1), 6461. https://doi.org/10.1038/s41467-023-41981-5 | spa |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | http://hdl.handle.net/11268/12330 | |
dc.description.abstract | The most prevalent genetic form of inherited arrhythmogenic cardiomyopathy (ACM) is caused by mutations in desmosomal plakophilin-2 (PKP2). By studying pathogenic deletion mutations in the desmosomal protein PKP2, here we identify a general mechanism by which PKP2 delocalization restricts actomyosin network organization and cardiac sarcomeric contraction in this untreatable disease. Computational modeling of PKP2 variants reveals that the carboxy-terminal (CT) domain is required for N-terminal domain stabilization, which determines PKP2 cortical localization and function. In mutant PKP2 cells the expression of the interacting protein MYH10 rescues actomyosin disorganization. Conversely, dominant-negative MYH10 mutant expression mimics the pathogenic CT–deletion PKP2 mutant causing actin network abnormalities and right ventricle systolic dysfunction. A chemical activator of non-muscle myosins, 4-hydroxyacetophenone (4-HAP), also restores normal contractility. Our findings demonstrate that activation of MYH10 corrects the deleterious effect of PKP2 mutant over systolic cardiac contraction, with potential implications for ACM therapy. | spa |
dc.description.sponsorship | MCIU grant BFU2016-75144-R | spa |
dc.description.sponsorship | PID2020-116935RB-I00 | spa |
dc.description.sponsorship | HR18-00304 “la Caixa” Banking Foundation grant | spa |
dc.description.sponsorship | 2017/RM01 Ayudas a la Investigación Cátedra Real Madrid-Universidad Europea” | spa |
dc.language.iso | eng | spa |
dc.rights | Attribution 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject.other | Cardiomiopatías | spa |
dc.title | MYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM) | spa |
dc.type | article | spa |
dc.description.impact | 16.6 Q1 JCR 2022 | spa |
dc.description.impact | 5.116 Q1 SJR 2022 | spa |
dc.description.impact | No data IDR 2022 | spa |
dc.identifier.doi | 10.1038/s41467-023-41981-5 | |
dc.rights.accessRights | openAccess | spa |
dc.subject.unesco | Enfermedad cardiovascular | spa |
dc.subject.unesco | Medicina preventiva | spa |
dc.subject.unesco | Genética humana | spa |
dc.description.filiation | UEM | spa |
dc.relation.publisherversion | https://doi.org/10.1038/s41467-023-41981-5 | spa |
dc.peerreviewed | Si | spa |