Light Chain AmyloidosiseInduced Autophagy Is Mediated by the Foxo3a/Beclin-1 Pathway in Cardiomyocytes

Cardiac amyloidosis is a disease in which the extracellular space of the heart is deposited with and infiltrated by amyloid fibrillar material, and light chain (LC) amyloidosis (AL) is the most serious form of the disease. AL is caused by the overproduction and aggregation of monoclonal immunoglobulin LCs produced by bone marrow plasma cells. Studies have shown that the initial response at a subcellular level to the toxicity of AL is lysosomal dysfunction with impaired autophagy, elevated reactive oxygen species, cellular dysfunction, and cellular death. Therefore, we speculate that the multiple myeloma complicated by cardiac amyloidosis is due to the deposition of lambda LC fibrils in cardiomyocytes, leading to dysregulation of autophagy and cell death. We constructed BACN1 siRNA or FOXO3A siRNA and transfected them into H9c2 cells. We detected changes in oxidative stress- and autophagy-related markers. Our results show that monoclonal immunoglobulin lambda LCs can form amyloid aggregates, which are cytotoxic to cardiomyocytes. lambda LC fibrils deposit on the cell surface, causing oxidative stress and excessive autophagy by increasing Beclin-1 expression and the LC3 II/LC3 I ratio and decreasing p62 expression, ultimately inducing cell death. Beclin-1 knockdown reversed the increase in the LC3 II/LC3 I ratio and the decrease in p62 induced by LC fibrils, while suppressing overactivated autophagy and oxidative stress. Furthermore, LCs reduce the expression of p-Foxo3a (Ser253) (inactive) and promote Foxo3a translocation into the nucleus to perform transcriptional activity, which induces autophagyrelated gene overexpression. Silencing Foxo3a can suppress excessive autophagy induced by LC fibrils and protect cells from death. In summary, the results showed that the cytotoxicity of amyloid fibrils formed by lambda LCs on cardiomyocytes is triggered by excessive autophagy and is mediated through the Foxo3a/Beclin-1 pathway. (c) 2022 THE AUTHORS. Published by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).