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Proteotoxicity in cardiac amyloidosis: Amyloidogenic light chains affect the levels of intracellular proteins in human heart cells

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dc.contributor.author Imperlini, Esther
dc.contributor.author Gnecchi, Massimiliano
dc.contributor.author Rognoni, Paola
dc.contributor.author Sabidó Aguadé, Eduard, 1981-
dc.contributor.author Ciuffreda, Maria Chiara
dc.contributor.author Palladini, Giovanni
dc.contributor.author Espadas, Guadalupe
dc.contributor.author Mancuso, Francesco M.
dc.contributor.author Bozzola, Margherita
dc.contributor.author Malpasso, Giuseppe
dc.contributor.author Valentini, Veronica
dc.contributor.author Palladini, Giuseppina
dc.contributor.author Orrù, Stefania
dc.contributor.author Ferraro, Giovanni
dc.contributor.author Milani, Paolo
dc.contributor.author Perlini, Stefano
dc.contributor.author Salvatore, Francesco
dc.contributor.author Merlini, Giampaolo
dc.contributor.author Lavatelli, Francesca
dc.date.accessioned 2018-07-18T07:59:05Z
dc.date.available 2018-07-18T07:59:05Z
dc.date.issued 2017
dc.identifier.citation Imperlini E, Gnecchi M, Rognoni P, Sabidò E, Ciuffreda MC, Palladini G et al. Proteotoxicity in cardiac amyloidosis: amyloidogenic light chains affect the levels of intracellular proteins in human heart cells. Sci Rep. 2017 Nov 15;7(1):15661. DOI: 10.1038/s41598-017-15424-3
dc.identifier.issn 2045-2322
dc.identifier.uri http://hdl.handle.net/10230/35186
dc.description.abstract AL amyloidosis is characterized by widespread deposition of immunoglobulin light chains (LCs) as amyloid fibrils. Cardiac involvement is frequent and leads to life-threatening cardiomyopathy. Besides the tissue alteration caused by fibrils, clinical and experimental evidence indicates that cardiac damage is also caused by proteotoxicity of prefibrillar amyloidogenic species. As in other amyloidoses, the damage mechanisms at cellular level are complex and largely undefined. We have characterized the molecular changes in primary human cardiac fibroblasts (hCFs) exposed in vitro to soluble amyloidogenic cardiotoxic LCs from AL cardiomyopathy patients. To evaluate proteome alterations caused by a representative cardiotropic LC, we combined gel-based with label-free shotgun analysis and performed bioinformatics and data validation studies. To assess the generalizability of our results we explored the effects of multiple LCs on hCF viability and on levels of a subset of cellular proteins. Our results indicate that exposure of hCFs to cardiotropic LCs translates into proteome remodeling, associated with apoptosis activation and oxidative stress. The proteome alterations affect proteins involved in cytoskeletal organization, protein synthesis and quality control, mitochondrial activity and metabolism, signal transduction and molecular trafficking. These results support and expand the concept that soluble amyloidogenic cardiotropic LCs exert toxic effects on cardiac cells.
dc.description.sponsorship This work was supported by the PRIME-XS project, grant agreement number 262067, funded by the European Union 7th Framework Programme; the Italian Ministry of Health (GR-2010-2317596); Associazione Italiana per la Ricerca sul Cancro special program “5 per mille” (number 9965); Fondazione Cariplo (2013-0964, 2015-0591 and 2016-0489); the Italian Ministry of Health, research target project “Cardiac amyloidosis: molecular mechanism and innovative therapies for a challenging aging” (RF-2013-02355259); POR Campania FSE 2007-2013, Project DIAINTECH; and by Grant PON03PE_00060_2 and PON03PE_00060_7 (Campania - Bioscience) from the Italian Ministry of University and Research. The CRG/UPF Proteomics Unit is part of the “Plataforma de Recursos Biomoleculares y Bioinformáticos (ProteoRed)” supported by grant PT13/0001 of ISCIII and Spanish Ministry of Economy and Competitiveness. We acknowledge support of the Spanish Ministry of Economy and Competitiveness, “Centro de Excelencia Severo Ochoa 2013-2017”, SEV-2012-0208, and from “Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat de Catalunya” (2014SGR678).
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Nature Publishing Group
dc.relation.ispartof Scientific Reports. 2017 Nov 15;7(1):15661
dc.rights © The Author(s) 2017. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/./licenses/by/4.0/.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Proteotoxicity in cardiac amyloidosis: Amyloidogenic light chains affect the levels of intracellular proteins in human heart cells
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1038/s41598-017-15424-3
dc.subject.keyword Molecular medicine
dc.subject.keyword Proteomic analysis
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/262067
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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