Role of stanniocalcin1 in immunoglobulin light chain amyloidotic cardiomyopathy
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Approximately half of patients with immunoglobulin light chain amyloidosis (AL) have cardiac involvement, usually presenting as diastolic dysfunction and heart failure. Despite progress in diagnosis and treatment of AL cardiomyopathy, prognosis is poor for many patients, highlighting the necessity for a better understanding of AL cardiomyopathy pathogenesis. Work from our laboratory has shown that amyloidogenic light chains (AL-LC) exhibit direct cardiotoxicity with activation of a non-canonical p38a MAPK signaling and generation of reactive oxygen species leading to oxidative stress, contractile dysfunction, and cell death. The goal of this work was to further determine the molecular mechanisms underlying the pathogenesis of AL cardiomyopathy. Stanniocalcin1 (STC1) has been implicated in several critical cellular processes important for the development of cardiomyopathy. In this thesis project, we utilized gain and loss of function approaches to define the role of STC1 in regulating AL-LC induced cellular dysfunction and cell death. Overexpression of STC1 using adenoviral mediated gene transfer or recombinant protein was sufficient to cause contractile dysfunction and cell death both in vitro and in vivo. Conversely, genetic silencing of STC1 using shRNA in isolated cardiomyocytes or morpholinos in vivo in a zebrafish model of AL-LC induced cardiotoxicity both demonstrated the requirement of STC1 for AL-LC mediated deleterious cardiac dysfunction. Data from immunocytochemistry and protein fractionation further revealed that STC1 was localized to the mitochondria in isolated cardiomyocytes. Using an integrated approach, we further demonstrated that STC1 dysregulated the process of mitochondrial autophagy, an essential cellular process, which was found to be both necessary and sufficient for AL-LC induced cell death. Collectively, this work demonstrated that AL-LC induced cardiac dysfunction was mediated via STC1 and subsequent dysregulation of mitochondrial autophagy. This novel pathway may represent a new target for the treatment of AL cardiomyopathy.
Thesis (Ph.D.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at firstname.lastname@example.org. Thank you.