Mishra, S., Guan, J., Plovie, E., Seldin, D.C., Connors, L.H., Merlini, G., Falk, R.H., MacRae, C.A., and Liao, R. (2013) Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish. American journal of physiology. Heart and circulatory physiology. 305(1):H95-H103.
Systemic amyloid light-chain (AL) amyloidosis is associated with a rapidly progressive and fatal cardiomyopathy resulting
from the direct cardiotoxic effects of circulating AL-light-chain (AL-LC) proteins and the indirect effects of amyloid fibril
tissue infiltration. Cardiac amyloidosis is resistant to standard heart failure therapies, and to date there are limited treatment
options for these patients. The mechanisms underlying the development of cardiac amyloidosis and AL-LC cardiotoxicity are
largely unknown, and their study has been limited by the lack of a suitable in vivo model system. Herein we establish an in
vivo zebrafish model of human AL-LC induced cardiotoxicity. AL-LC, isolated from AL cardiomyopathy patients, or control non-amyloidogenic
LC protein isolated from multiple myeloma patients (Con-LC), were directly injected into the circulation of zebrafish at 48
hours post fertilization. AL-LC injection resulted in impaired cardiac function, pericardial edema and increased cell death
relative to Con-LC, culminating in compromised survival with 100% mortality within 2 weeks, independent of amyloid fibril
deposition. Prior work has implicated non-canonical p38MAPK activation in the pathogenesis of AL-LC induced cardiotoxicity
and p38MAPK inhibition via SB203580 rescued AL-LC induced cardiac dysfunction and cell death, and attenuated mortality in
zebrafish. This in vivo zebrafish model of AL-LC cardiotoxicity demonstrates that antagonism of p38MAPK within the AL-LC cardiotoxic
signaling response may serve to improve cardiac function and mortality in AL amyloid cardiomyopathy. Furthermore, this in
vivo model system will allow for further study of the molecular underpinnings of amyloid cardiotoxicity and identification
of novel therapeutic strategies.