Abstract
BackgroundDoxorubicin (DOX) is one of the most potent chemotherapy agents. Its clinical use however, is restricted due to the severe risk of cardiotoxicity, presumably attributed to high levels of reactive oxygen species (ROS) leading to cardiomyocyte death. Telomerase prevents cell death through maintaining telomeres. In addition, telomerase has non‐canonical, anti‐apoptotic and pro‐survival traits, likely owing to detoxification of ROS. However, telomerase is silenced in adult murine and human hearts.PurposeTo test whether pharmacological reactivation of telomerase may be effective as a therapeutic strategy to prevent doxorubicin‐induced cardiotoxicity.Methods and ResultsWe used a AAV9‐based gene therapy approach to reinstate telomerase expression in cardiomyocytes in a mouse model of chronic DOX‐induced cardiotoxicity. Telomerase treated mice presented with preserved heart weights in comparison to AAV‐empty controls after DOX treatment. Histopathological analyses revealed that this rescue was accompanied by preserved cardiomyocyte size and reduced apoptosis rates. This was also reflected by improved cardiac function parameters determined by echocardiography and Millar catheterization. At the molecular level we observed altered mitochondria morphology and reduced mitochondrial fission in response to telomerase expression. In line, Western blotting post telomerase reactivation revealed lower levels of the mitochondrial fission protein Drp1, which plays a known role in cardioprotection. Complementary in vitro experiments confirmed anti‐apoptotic effects of telomerase in DOX treated human induced pluripotent stem cell (hiPSC)‐derived cardiomyocytes.ConclusionOur data suggest that cardiac‐specific telomerase reactivation could be a novel strategy for the prevention of doxorubicin‐induced cardiotoxicity in cancer survivors.Support or Funding InformationThis work was supported by the DFG (BA5631/2‐1 to CB) and ERA‐CVD Network (EXPERT grant to TT).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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