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.
| Original language | English |
|---|---|
| Pages (from-to) | 15661 |
| Journal | Scientific Reports |
| Volume | 7 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Nov 15 2017 |
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Proteotoxicity in cardiac amyloidosis : amyloidogenic light chains affect the levels of intracellular proteins in human heart cells. / Imperlini, Esther; Gnecchi, Massimiliano; Rognoni, Paola; Sabidò, Eduard; Ciuffreda, Maria Chiara; Palladini, Giovanni; Espadas, Guadalupe; Mancuso, Francesco Mattia; Bozzola, Margherita; Malpasso, Giuseppe; Valentini, Veronica; Palladini, Giuseppina; Orrù, Stefania; Ferraro, Giovanni; Milani, Paolo; Perlini, Stefano; Salvatore, Francesco; Merlini, Giampaolo; Lavatelli, Francesca.
In: Scientific Reports, Vol. 7, No. 1, 15.11.2017, p. 15661.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Proteotoxicity in cardiac amyloidosis
T2 - amyloidogenic light chains affect the levels of intracellular proteins in human heart cells
AU - Imperlini, Esther
AU - Gnecchi, Massimiliano
AU - Rognoni, Paola
AU - Sabidò, Eduard
AU - Ciuffreda, Maria Chiara
AU - Palladini, Giovanni
AU - Espadas, Guadalupe
AU - Mancuso, Francesco Mattia
AU - Bozzola, Margherita
AU - Malpasso, Giuseppe
AU - Valentini, Veronica
AU - Palladini, Giuseppina
AU - Orrù, Stefania
AU - Ferraro, Giovanni
AU - Milani, Paolo
AU - Perlini, Stefano
AU - Salvatore, Francesco
AU - Merlini, Giampaolo
AU - Lavatelli, Francesca
PY - 2017/11/15
Y1 - 2017/11/15
N2 - 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.
AB - 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.
U2 - 10.1038/s41598-017-15424-3
DO - 10.1038/s41598-017-15424-3
M3 - Article
C2 - 29142197
VL - 7
SP - 15661
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
ER -