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.