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, Estherca
• dc.contributor.author Gnecchi, Massimilianoca
• dc.contributor.author Rognoni, Paolaca
• dc.contributor.author Sabidó Aguadé, Eduard, 1981-ca
• dc.contributor.author Ciuffreda, Maria Chiaraca
• dc.contributor.author Palladini, Giovannica
• dc.contributor.author Espadas, Guadalupeca
• dc.contributor.author Mancuso, Francesco M.ca
• dc.contributor.author Bozzola, Margheritaca
• dc.contributor.author Malpasso, Giuseppeca
• dc.contributor.author Valentini, Veronicaca
• dc.contributor.author Palladini, Giuseppinaca
• dc.contributor.author Orrù, Stefaniaca
• dc.contributor.author Ferraro, Giovannica
• dc.contributor.author Milani, Paoloca
• dc.contributor.author Perlini, Stefanoca
• dc.contributor.author Salvatore, Francescoca
• dc.contributor.author Merlini, Giampaoloca
• dc.contributor.author Lavatelli, Francescaca
• dc.date.accessioned 2018-07-18T07:59:05Z
• dc.date.available 2018-07-18T07:59:05Z
• dc.date.issued 2017
• 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.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.doi http://dx.doi.org/10.1038/s41598-017-15424-3
• dc.identifier.issn 2045-2322
• dc.identifier.uri http://hdl.handle.net/10230/35186
• dc.language.iso eng
• dc.publisher Nature Publishing Groupca
• dc.relation.ispartof Scientific Reports. 2017 Nov 15;7(1):15661
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/262067
• 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.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Molecular medicine
• dc.subject.keyword Proteomic analysis
• dc.title Proteotoxicity in cardiac amyloidosis: Amyloidogenic light chains affect the levels of intracellular proteins in human heart cellsca
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion