title: Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity.
abstract: Immunoglobulin light chain (LC) amyloidosis (AL) results from overproduction of circulating amyloidogenic LC proteins and subsequent amyloid fibril deposition in organs. Mortality in AL amyloidosis patients is highly associated with a rapidly progressive AL cardiomyopathy, marked by profound impairment of diastolic and systolic cardiac function and significant early mortality. While myocardial fibril deposition contributes to the severe diastolic dysfunction seen in AL cardiomyopathy patients, the degree of fibril deposition has not been found to correlate with prognosis. Previously, we and others showed a direct cardiotoxic effect of amyloidogenic LC proteins (AL-LC), which may contribute to the pathophysiology and mortality observed in AL cardiomyopathy patients. However, the mechanisms underlying AL-LC related cardiotoxicity remain unknown. Mammalian stanniocalcin1 (STC1) is associated with a number of cellular processes including oxidative stress and cell death. Herein, we find that STC1 expression is elevated in cardiac tissue from AL cardiomyopathy patients, and is induced in isolated cardiomyocytes in response to AL-LC, but not non-amyloidogenic LC. STC1 overexpression in vitro recapitulates the pathophysiology of AL-LC mediated cardiotoxicity, with increased ROS production, contractile dysfunction and cell death. Overexpression of STC1 in vivo results in significant cardiac dysfunction and cell death. Genetic silencing of STC1 prevents AL-LC induced cardiotoxicity in cardiomyocytes and protects against AL-LC induced cell death and early mortality in zebrafish. The cardiotoxic effects of STC1 appears to be mediated via mitochondrial dysfunction as indicated by loss of mitochondrial membrane potential, ROS production and increased mitochondrial calcium levels. Collectively, this work identifies STC1 as a critical determinant of AL-LC cardiotoxicity.
authors: Divisions of Cardiovascular Medicine and Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, NRB 431, Boston, MA 02115, USA.
authors: Jian
authors: J
authors: Guan
authors: Shikha
authors: S
authors: Mishra
authors: Jianru
authors: J
authors: Shi
authors: Eva
authors: E
authors: Plovie
authors: Yiling
authors: Y
authors: Qiu
authors: Xin
authors: X
authors: Cao
authors: Davide
authors: D
authors: Gianni
authors: Bingbing
authors: B
authors: Jiang
authors: Federica
authors: F
authors: Del Monte
authors: Lawreen H
authors: LH
authors: Connors
authors: David C
authors: DC
authors: Seldin
authors: Francesca
authors: F
authors: Lavatelli
authors: Paola
authors: P
authors: Rognoni
authors: Giovanni
authors: G
authors: Palladini
authors: Giampaolo
authors: G
authors: Merlini
authors: Rodney H
authors: RH
authors: Falk
authors: Marc J
authors: MJ
authors: Semigran
authors: G William
authors: GW
authors: Dec
authors: Calum A
authors: CA
authors: Macrae
authors: Ronglih
authors: R
authors: Liao
mesh_terms: D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007147:Immunoglobulin Light Chains / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish
chemical_list: D006023:Glycoproteins; D007147:Immunoglobulin Light Chains; C051795:teleocalcin
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