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

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.