Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish
- Authors
- Mishra, S., Guan, J., Plovie, E., Seldin, D.C., Connors, L.H., Merlini, G., Falk, R.H., MacRae, C.A., and Liao, R.
- ID
- ZDB-PUB-130604-11
- Date
- 2013
- Source
- American journal of physiology. Heart and circulatory physiology 305(1): H95-H103 (Journal)
- Registered Authors
- MacRae, Calum A.
- Keywords
- amyloidosis, apoptosis, in vivo model of cardiovascular disease, p38MAPK
- MeSH Terms
-
- Amyloid/toxicity*
- Amyloidosis/metabolism
- Animals
- Apoptosis*
- Cardiomyopathies/chemically induced
- Cardiomyopathies/pathology
- Cardiomyopathies/physiopathology
- Cardiotoxins/toxicity*
- Death
- Disease Models, Animal
- Heart/drug effects
- Heart/physiopathology*
- Humans
- MAP Kinase Signaling System
- Myocardium/metabolism
- Myocardium/pathology*
- Zebrafish
- p38 Mitogen-Activated Protein Kinases/metabolism
- PubMed
- 23624626 Full text @ Am. J. Physiol. Heart Circ. Physiol.
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.