title: Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish.
abstract: Systemic amyloid light-chain (AL) amyloidosis is associated with rapidly progressive and fatal cardiomyopathy resulting from the direct cardiotoxic effects of circulating AL light chain (AL-LC) proteins and the indirect effects of AL 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. Here, we establish an in vivo zebrafish model of human AL-LC-induced cardiotoxicity. AL-LC isolated from AL cardiomyopathy patients or control nonamyloidogenic LC protein isolated from multiple myeloma patients (Con-LC) was directly injected into the circulation of zebrafish at 48 h postfertilization. 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 wk, independent of AL fibril deposition. Prior work has implicated noncanonical p38 MAPK activation in the pathogenesis of AL-LC-induced cardiotoxicity, and p38 MAPK inhibition via SB-203580 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 p38 MAPK within the AL-LC cardiotoxic signaling response may serve to improve cardiac function and mortality in AL cardiomyopathy. Furthermore, this in vivo model system will allow for further study of the molecular underpinnings of AL cardiotoxicity and identification of novel therapeutic strategies.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Shikha
authors.initials: S
authors.lastname: Mishra
authors.forename: Jian
authors.initials: J
authors.lastname: Guan
authors.forename: Eva
authors.initials: E
authors.lastname: Plovie
authors.forename: David C
authors.initials: DC
authors.lastname: Seldin
authors.forename: Lawreen H
authors.initials: LH
authors.lastname: Connors
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.forename: Rodney H
authors.initials: RH
authors.lastname: Falk
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
mesh_terms: D000682:Amyloid / Q000633:toxicity*; D000686:Amyloidosis / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D054715:Cardiotoxins / Q000633:toxicity*; D003643:Death; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D020935:MAP Kinase Signaling System; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D015027:Zebrafish; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000682:Amyloid; D054715:Cardiotoxins; C033048:amyloid protein AR, human; D048051:p38 Mitogen-Activated Protein Kinases
keywords: amyloidosis; apoptosis; in vivo model cardiovascular disease; p38 mitogen-activated protein kinase