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

被引：122

作者：

Diomede, Luisa ^{[1
]}

Rognoni, Paola ^{[2
]}

Lavatelli, Francesca ^{[2
]}

Romeo, Margherita ^{[1
]}

del Favero, Elena ^{[3
]}

Cantu, Laura ^{[3
]}

Ghibaudi, Elena ^{[4
]}

di Fonzo, Andrea ^{[2
]}

Corbelli, Alessandro ^{[5
,6
,7
]}

Fiordaliso, Fabio ^{[5
]}

Palladini, Giovanni ^{[2
,8
]}

Valentini, Veronica ^{[2
]}

Perfetti, Vittorio ^{[9
]}

Salmona, Mario ^{[1
]}

Merlini, Giampaolo ^{[2
,8
]}

机构：

[1] IRCCS Ist Ric Farmacol Mario Negri, Dept Mol Biochem & Pharmacol, I-20156 Milan, Italy

[2] Fdn Ist Ricovero & Cura Carattere Sci Policlin Sa, Amyloid Res & Treatment Ctr, Pavia, Italy

[3] Univ Milan, Lab Interdisciplinare Tecnol Avanzate, Dept Med Biotechnol & Translat Med, Segrate, Italy

[4] Univ Turin, Dept Chem, Turin, Italy

[5] IRCCS Ist Ric Farmacol Mario Negri, Bioimaging Unit, Dept Cardiovasc Res, I-20156 Milan, Italy

[6] Fdn Ist Ricovero & Cura Carattere Sci Ca Granda O, Renal Res Lab, Milan, Italy

[7] Fdn Amico Ric Malattie Renali, Milan, Italy

[8] Univ Pavia, Dept Mol Med, I-27100 Pavia, Italy

[9] Fdn Ist Ricovero & Cura Carattere Sci Policlin Sa, Med Oncol Unit, Pavia, Italy

来源：

BLOOD | 2014年 / 123卷 / 23期

基金：

美国国家卫生研究院;

关键词：

AL AMYLOIDOSIS; NATRIURETIC PEPTIDE; ORGAN INVOLVEMENT; GERMLINE GENE; BETA; DYSFUNCTION; TETRACYCLINES; POLYPHENOLS; SUPEROXIDE; MECHANISMS;

D O I：

10.1182/blood-2013-10-525634

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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. We have exploited the nematode Caenorhabditis elegans as a novel tool, because its pharynx is evolutionarily related to the vertebrate heart. Our data demonstrate 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.

引用

页码：3543 / 3552

页数：10

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