Poor prognosis and limited therapeutic options characterize immunoglobulin light-chain (AL) amyloidosis with major heart involvement. Reliable experimental models are needed to study light-chain (LC)/heart interactions and to explore strategies for prevention of cardiac damage.Wehave exploited the nematode Caenorhabditis elegans as a novel tool, because its pharynx is evolutionarily related to the vertebrate heart. Our datademonstrate that the pharyngeal pumping of C elegans is significantly and selectively reduced by LCs from AL patients suffering from cardiomyopathy, but not by amyloid LCs with different organ tropism or nonamyloidogenic LCs from multiple myeloma. This functional alteration is dependent on the LC concentration and results in persistent pharyngeal dysfunction and in a significant reduction of the worms’ lifespan. These manifestations are paralleled by an increase of mitochondrial reactive oxygen species and can be prevented by treatment with antioxidant agents. In conclusion, these data indicate that this nematode-based assay is a promising surrogate model for investigating the heart-specific toxicity of amyloidogenic LCs and for a rapid screening of new therapeutic strategies.

A Caenorhabditis elegans-based assay recognizes immunoglobulin light chains causing heart amyloidosis

GHIBAUDI, Elena Maria;
2014

Abstract

Poor prognosis and limited therapeutic options characterize immunoglobulin light-chain (AL) amyloidosis with major heart involvement. Reliable experimental models are needed to study light-chain (LC)/heart interactions and to explore strategies for prevention of cardiac damage.Wehave exploited the nematode Caenorhabditis elegans as a novel tool, because its pharynx is evolutionarily related to the vertebrate heart. Our datademonstrate that the pharyngeal pumping of C elegans is significantly and selectively reduced by LCs from AL patients suffering from cardiomyopathy, but not by amyloid LCs with different organ tropism or nonamyloidogenic LCs from multiple myeloma. This functional alteration is dependent on the LC concentration and results in persistent pharyngeal dysfunction and in a significant reduction of the worms’ lifespan. These manifestations are paralleled by an increase of mitochondrial reactive oxygen species and can be prevented by treatment with antioxidant agents. In conclusion, these data indicate that this nematode-based assay is a promising surrogate model for investigating the heart-specific toxicity of amyloidogenic LCs and for a rapid screening of new therapeutic strategies.
123
3543
3552
http://bloodjournal.hematologylibrary.org/
heart amyloidosis; redox cycling; diagnostic assay
L. Diomede;P. Rognoni;F. Lavatelli;M. Romeo;E. del Favero;L. Cantu;E. Ghibaudi;A. di Fonzo;A. Corbelli;F. Fiordaliso;G. Palladini;V. Valentini;V. Perfetti;M. Salmona;G. Merlini
File in questo prodotto:
File Dimensione Formato  
Blood 2014 Diomede - final.pdf

Accesso riservato

Descrizione: Articolo principale
Tipo di file: PDF EDITORIALE
Dimensione 970.19 kB
Formato Adobe PDF
970.19 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
Blood-2014-Diomede-blood-2013-10-525634.pdf

Accesso aperto

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 1.24 MB
Formato Adobe PDF
1.24 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/151896
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 92
  • ???jsp.display-item.citation.isi??? 85
social impact