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Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity

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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.

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Acknowledgments

The authors thank Ms. Wendy Du at Carnegie Mellon University, Mr. Soeun Ngoy at the Brigham and Women’s Hospital (BWH) Cardiovascular Physiology Core, Ms. Gloria Chan at Boston University (BU) Amyloidosis Center for excellent technical assistances and Drs. Yingyi Zhang, Judith Gwathmey and Thomas E. Macgillivray for providing critical reagents. This work was supported, in part, by the National Institutes of Health (NIH), HL088533, HL086967, HL093148, HL099073 (R.L.), DK90696 (D.C.S.), AG031804 (L.H.C.), American Heart Association (C.A.M.), and the Cardiac Amyloidosis Program, BWH (R.H.F., R.L.) and the Gruss and Wildflower Foundations and the Amyloid Research Fund at BU (L.H.C., D.C.S.). G.M. is supported by Associazione Italiana per la Ricercasul Cancro Special Program 5× mille, Molecular Clinical Oncology. S.M. is supported by NIH T32 (T32HL007604).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 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

    Jian Guan, Shikha Mishra, Jianru Shi, Yiling Qiu, Xin Cao, Bingbing Jiang & Ronglih Liao

  2. Molecular Medicine Graduate Program, Boston University School of Medicine, Boston, MA, 02115, USA

    Jian Guan

  3. Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Thorn 11, 75 Francis Street, Boston, MA, 02115, USA

    Eva Plovie & Calum A. MacRae

  4. University of Massachusetts Medical School, Worcester, MA, USA

    Davide Gianni

  5. Cardiovascular Medicine, Department of Medicine, Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    Federica del Monte

  6. Amyloid Research and Treatment Program, Boston University School of Medicine, Boston, MA, USA

    Lawreen H. Connors & David C. Seldin

  7. Amyloid Research and Treatment Center, University of Pavia, Pavia, Italy

    Francesca Lavatelli, Paola Rognoni, Giovanni Palladini & Giampaolo Merlini

  8. Cardiac Amyloidosis Program, Brigham and Women’s Hospital, Boston, MA, USA

    Rodney H. Falk & Ronglih Liao

  9. Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Marc J. Semigran & G. William Dec Jr.

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  1. Jian Guan
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Guan, J., Mishra, S., Shi, J. et al. Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity. Basic Res Cardiol 108, 378 (2013). https://doi.org/10.1007/s00395-013-0378-5

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