Abstract 18865: A Novel in vivo Model of Amyloidogenic Light Chain Induced Cardiac Toxicity in Zebrafish
Over 50% of amyloidogenic light chain (AL) amyloidosis patients present with cardiac involvement, characterized by fibril deposition in cardiac tissue, resulting in a rapidly progressing, fatal cardiomyopathy. Aside from cardiac transplantation, there are currently no targeted pharmacologic treatments available for cardiac amyloidosis. This is largely attributed to our limited understanding of the underlying molecular mechanisms of this disease, compounded by the lack of an in vivo model to study disease mechanisms. Previous work from our laboratory demonstrated that human AL- light chain (LC) proteins exhibit an inherent cardiac toxicity via a p38/MAPK dependent pathway, independent of fibril formation. Here we demonstrate a novel in vivo model of AL-LC cardiotoxicity in zebrafish. Zebrafish embryos were treated with AL-LC, Control-LC (Con-LC) or vehicle (Veh), injected directly into circulation via cardiac puncture. Consistent with our previous findings, AL-LC treatment elicited an increase in p38 activation. This was accompanied by increased cardiac cell death, as measured by Bax/Bcl2 ratio and TUNEL staining of isolated zebrafish hearts. Additionally, AL-LC treated embryos exhibited a decrease in cardiac output. Strikingly, AL-LC treatment resulted in a marked loss of survival (Figure 1), with 100% mortality at 13 days. Our lab recently identified a major role for stanniocalcin1 (STC1) in the pathogenesis of AL-LC-induced cardiotoxicity. STC1 expression was significantly increased by AL-LC treatment, but not by Con-LC. Morpholino-mediated silencing of STC1 expression protected against AL-LC induced cardiotoxicity, preventing cardiac cell death and mortality.Collectively, this work establishes a novel zebrafish model of cardiac amyloidosis, and identifies STC1 as a critical determinant of AL-LC mediated toxicity, demonstrating its requirement in downstream signaling pathways associated with AL-LC induced cardiac toxicity. .
- © 2012 by American Heart Association, Inc.