Doxorubicin is one of the most potent chemotherapeutic agents. However, its clinical use is restricted due to the severe risk of cardiotoxicity, partially attributed to elevated production of reactive oxygen species (ROS). Telomerase canonically maintains telomeres during cell division but is silenced in adult hearts. In non-dividing cells such as cardiomyocytes, telomerase confers pro-survival traits, likely owing to the detoxification of ROS. Therefore, we hypothesized that pharmacological overexpression of telomerase may be used as a therapeutic strategy for the prevention of doxorubicin-induced cardiotoxicity. We used adeno-associated virus (AAV)-mediated gene therapy for long-term expression of telomerase in in vitro and in vivo models of doxorubicin-induced cardiotoxicity. Overexpression of telomerase protected the heart from doxorubicin-mediated apoptosis and rescued cardiac function, which was accompanied by preserved cardiomyocyte size. At the mechanistic level, we observed altered mitochondrial morphology and dynamics in response to telomerase expression. Complementary in vitro experiments confirmed the anti-apoptotic effects of telomerase overexpression in human induced pluripotent stem cell-derived cardiomyocytes after doxorubicin treatment. Strikingly, elevated levels of telomerase translocated to the mitochondria upon doxorubicin treatment, which helped to maintain mitochondrial function. Thus, telomerase gene therapy could be a novel preventive strategy for cardiotoxicity by chemotherapy agents such as the anthracyclines.

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.