Investigating the role of SIRT3 in doxorubicin induced dilated cardiomyopathy

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Tomczyk, Mateusz
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Doxorubicin (DOX) is an effective anthracycline anti-neoplastic agent used for the treatment of hematological and solid tumors. Advancements in cancer treatment over several decades have led to increased cancer remission and survival. However, high cumulative dosages of anthracycline chemotherapeutics put patients at risk for the development cardiovascular complications later in life. Specifically, DOX can induce the development of a progressive dilated cardiomyopathy characterized by reduced ventricular wall thickness which can lead to cardiac dysfunction and possibly heart failure. This generates a quandary where physicians must deliberate the consequences of halting cancer therapy prematurely at the expense of neoplastic cell growth and metastasis or administering cumulative dosages that put patients at risk for developing cardiotoxic side effects. The cardiotoxic effects of DOX are attributed to the production of reactive oxygen species and mitochondrial dysfunction. Previous work from our lab showed that in H9c2 rat cardiomyoblasts, DOX reduced protein Sirtuin 3 (SIRT3), the main mitochondrial lysine deacetylase. In the following dissertation we move our findings in vivo, using an animal model of chronic DOX treatment and transgenic mice that have cardiac expression of a truncated M3-SIRT3 and a full length mitochondrial localized M1-SIRT3, to show that SIRT3 expression in the heart can prevent cardiotoxic effects of DOX. Our first study focuses on investigating the effect of DOX on acetylation and SIRT3 regulation of SOD2, a mitochondrial enzyme involved in the detoxification of reactive oxygen species. Our subsequent work develops a narrative of DOX impaired cardiac metabolism. Using mass spectrometry methods, we identified that DOX altered the acetylation of Hydroxyacyl-CoA Dehydrogenase-α, a mitochondrial enzyme involved in the utilization of fatty acids, the main fuel source for the heart. This finding led us to perform a global lipidomic analysis of cardiac tissue revealing DOX reduced myocardial triglycerides in non-transgenic animals. Successively, we performed 1H-NMR spectroscopy and 18F-FDG PET to examine how DOX alters cardiac metabolites and cardiac glucose uptake. Our work embodies an important expansion in our understanding of the cardiometabolic dysfunction leading to DOX induced cardiotoxicity and how SIRT3 may be a potential therapeutic target for the prevention of chemotherapy induced dilated cardiomyopathy.
Sirtuin 3, Cardiotoxicity, Chemotherapy, Doxorubicin