Abstract 3602: Human Amyloidogenic Light Chains Induce Cellular Dysfunction and Oxidant Stress via p38MAPK Signaling Pathway
Primary (AL) amyloidosis is a plasma cell dyscrasia resulting in the clonal production of immunoglobulin light chain (LC) proteins and subsequent amyloid fibril deposition. Involvement of the heart results in amyloid cardiomyopathy with very poor prognosis. Previously, we have demonstrated a direct toxic effect of human amyloidogenic LC on cardiomyocyte function prior to amyloid fibril formation. The stress-activated kinase p38MAPK has been suggested to mediate cellular toxicity in other forms of amyloidosis. To determine whether LC associated with AL cardiomyopathy activates p38MAPK, phospho-p38 was detected in adult rat cardiomyocytes exposed to LC proteins (20μg/ml) isolated from the urine of patients with AL (Cardiac-LC) or multiple myeloma with no amyloid disease (Con-LC), or to vehicle control. We found that Cardiac-LC acutely activates p38MAPK in cardiomyocytes within 15 minutes of exposure relative to both Con-LC and vehicle. The requirement of p38MAPK for Cardiac-LC-induced ROS generation and subsequent cardiomyocyte dysfunction was investigated using SB203580, a pharmacological inhibitor of p38MAPK, or with adenoviral-mediated gene transfer of dominant-negative p38MAPK. In both experiments, Cardiac-LC-induced ROS was repressed, and an improvement in cell contractility was observed. Thus, our data suggest that the p38MAPK signaling cascade mediates cellular oxidant stress and cardiomyocyte dysfunction induced by Cardiac-LC.
Conclusion: Our data provide the first mechanistic insight into AL cardiomyopathy. Targeted therapies aimed at either inhibiting the p38MAPK pathway or increasing antioxidant capacity may prove beneficial in the treatment of this disease.