Molecular Mechanisms and Treatment of Primary Amyloid AL Cardiomyopathy

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DESCRIPTION (provided by applicant): Amyloidosis represents a group of human diseases in which protein precursors exhibit altered secondary structure and form insoluble protein aggregates in tissues. Primary amyloidosis (AL) is the most common systemic amyloidosis and is initiated by the clonal production of immunoglobulin light chain (LC) proteins by plasma cells. While AL aggregates may form in numerous organs, cardiac deposition is associated with the worst prognosis. The resulting amyloid AL cardiomyopathy is unique in that it is not responsive to standard heart failure regimens and is accompanied by greater than 50% mortality over 5 years, comparable to the most aggressive types of cancers. To date, there is no treatment for AL cardiomyopathy, other than orthotopic transplantation, owing to the lack of understanding of the molecular mechanisms that underlie this disease process. During the past funding cycle, our laboratory has provided the first mechanistic insight into the pathogenesis of AL cardiomyopathy and demonstrated that human amyloidogenic LC (AL-LC) provoke a cardiotoxic effects via activation of non-canonical p38 MAPK signaling cascade and subsequently lead to increase cellular oxidant stress, altered calcium homeostasis, impaired cellular contractility, and, eventually, cell death. Through the use of unbiased genomics we have recently identified a novel cardiomyocyte regulator of LC toxicity, stanniocalcin-1 (STC1), from whole genome transcriptomic analyses of AL-LC treated cardiomyocytes and explanted human hearts with AL cardiomyopathy. Moreover, we find that upregulation of STC1 is dependent upon upstream p38 MAPK activation, and that STC1 localizes to the cardiomyocyte mitochondria, where it induces ROS generation, cellular dysfunction and death in isolated adult cardiomyocytes via the inhibition of autophagy clearance. With our prior findings and preliminary data, in this competitive renewal application, we propose to test our central hypothesis that that circulating AL-LC imparts a deleterious effect on cardiomyocytes via STC1 impairment of mitochondrial function and dysregulation of cellular autophagy. Utilizing a multidisciplinary approach of molecular and cellular biology, biochemistry, and physiology, coupled with isolated cardiomyocyte and in vivo mouse models, we will determine the necessity and sufficiency of STC1 (Aim 1) and the role of autophagy (Aim 2) in AL-LC induced deleterious events. This work represents our continued intensive investigation of the mechanism underlying amyloid cardiomyopathy.