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.
Highlights
AL amyloidosis is characterized by widespread deposition of immunoglobulin light chains (LCs) as amyloid fibrils
Three experimental conditions were compared: human cardiac fibroblasts (hCFs) exposed to a monoclonal amyloidogenic cardiotoxic light chain (CardioLC-1 in Table 1), hCFs exposed to a control monoclonal LC from a patient with multiple myeloma (MMLC-2 in Table 1), and hCFs not exposed to LCs (Control)
In this study we sought to describe the molecular changes occurring in hCFs exposed in vitro to exogenous LCs causing AL cardiomyopathy, through the characterization of their cellular proteome
Summary
AL amyloidosis is characterized by widespread deposition of immunoglobulin light chains (LCs) as amyloid fibrils. 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. The systems used in this setting include cultured human and rodent cardiac cells[9,10,11,12,13,15,16,17] and the recently established animal models C. elegans and zebrafish[11,14] These systems share a crucial feature, namely, the fact that damage is exerted by LCs that are cardiotropic in patients, and not by those that target other organs or by non-amyloidogenic LCs. exposure to exogenous cardiotropic LCs at concentrations commonly observed in patients’ sera leads to functional and cellular dysfunction. The rationale of the present study is that altered protein expression profiles may be associated with the proteotoxicity of LCs, and that the description of such changes would cast light on the molecular events associated to soluble LC-induced damage
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