Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity

Jian Guan, Shikha Mishra, Jianru Shi, Eva Plovie, Yiling Qiu, Xin Cao, Davide Gianni, Bingbing Jiang, Federica Del Monte, Lawreen H. Connors, David C. Seldin, Francesca Lavatelli, Paola Rognoni, Giovanni Palladini, Giampaolo Merlini, Rodney H. Falk, Marc J. Semigran, G. William Dec, Calum A. MacRae, Ronglih Liao

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number378
JournalBasic Research in Cardiology
Volume108
Issue number5
DOIs
Publication statusPublished - 2013

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Keywords

  • Amyloidosis
  • Cardiac toxicity
  • Cardiomyopathy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

Guan, J., Mishra, S., Shi, J., Plovie, E., Qiu, Y., Cao, X., Gianni, D., Jiang, B., Del Monte, F., Connors, L. H., Seldin, D. C., Lavatelli, F., Rognoni, P., Palladini, G., Merlini, G., Falk, R. H., Semigran, M. J., Dec, G. W., MacRae, C. A., & Liao, R. (2013). Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity. Basic Research in Cardiology, 108(5), [378]. https://doi.org/10.1007/s00395-013-0378-5