Imperlini, EstherGnecchi, MassimilianoRognoni, PaolaSabidó Aguadé, Eduard, 1981-Ciuffreda, Maria ChiaraPalladini, GiovanniEspadas, GuadalupeMancuso, Francesco M.Bozzola, MargheritaMalpasso, GiuseppeValentini, VeronicaPalladini, GiuseppinaOrrù, StefaniaFerraro, GiovanniMilani, PaoloPerlini, StefanoSalvatore, FrancescoMerlini, GiampaoloLavatelli, Francesca2018-07-182018-07-182017Imperlini 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/s41598-017-15424-32045-2322http://hdl.handle.net/10230/35186AL 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.application/pdfeng© 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/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41598-017-15424-3Molecular medicineProteomic analysisinfo:eu-repo/semantics/openAccess