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Carvedilol protection involves the mitochondrial deacetylase Sirt3 in mitigating Doxorubicin‐induced Cardiomyocyte Injury

Although anthracyclines such as doxorubicin are highly effective chemotherapeutic agents and widely used for various malignancies, their use in the clinic is accompanied by major cardiovascular events. Cardiotoxicity is a well‐recognized and unpredictable consequence of anthracycline therapy that may be permanent and progressive, leading to heart failure in some patients while severely impacting quality of life. The pathophysiology of anthracycline‐induced cardiotoxicity has not been fully elucidated but the most widely accepted hypothesis is the increased reactive oxygen species (ROS) generated by anthracyclines. Data from our lab as well as other recent studies support an alternative model involving mitochondrial dysfunction perpetuated by anthracycline‐induced dysregulation of mitochondrial protein modifications. The mitochondrial deacetylase Sirt3 has been suggested to play a role in cardio‐protection. Carvedilol, a beta‐blocker, had previously been shown to mitigate anthracycline‐induced mitochondrial dysfunction and although the mechanism is unknown, data from our lab suggest involvement with Sirt3. To explore this further, rat embryonic cardiomyocytes (H9c2 cells) devoid of Sirt3 expression were either treated with doxorubicin or pretreated with carvedilol followed by doxorubicin treatment before downstream assays were performed. Protein expression and/or activity assays were performed to assess proteins involved in apoptosis and mitochondrial function and stability including caspase3 and the Sirt3 target Mn/SOD. MitoSOX assay was done to assess mitochondrial ROS generation. Our results suggest that carvedilol prevents or reverses the anthracycline‐induced inhibition of Sirt3, a protein responsible for activating mitochondrial proteins involved with metabolic processes and maintenance of ROS. Further and ongoing studies in the lab will access the role of Sirt3 in cardio‐protection in vivo.