Telomerase therapy attenuates cardiotoxic effects of doxorubicin

Abstract

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.

Progress in cardiac research: from rebooting cardiac regeneration to a complete cell atlas of the heart

“…Another thought-provoking therapeutic approach has been recently proposed to prevent anthracycline-induced cardiomyopathy by means of gene therapy with pharmacological upregulation of telomerase in cardiomyocytes. 68 The rationale of this approach was based on the significant pro-survival results obtained following AAV9 gene therapy for telomerase ( Tert ) cardiomyocyte overexpression after MI in the adult mouse, 69 along with the TERT polymerase’s function in eliminating mitochondrial ROS in compromised arterioles of patients with coronary artery disease. 70 By translating such findings in the anthracycline cardiotoxicity scenario, the authors provided new understandings on the ectopic expression of TERT targeting mitochondrial mechanisms, thus offering a possible therapeutic approach to promote cardiomyocyte preservation.…”

Profile, treatment patterns, and influencing factors of anthracycline use in breast cancer patients in China: A nation‐wide multicenter study

“…Emerging studies emphasized the adverse effects of anthracyclines, and further efforts have been made to prevent and treat them, especially against cardiotoxicity 19–21 . Several drugs and/or therapies are proposed as cardioprotective agents/approaches during the treatment with ABC, such as dexrazoxane, β‐blockers, ACE inhibitors, telomerase therapy, and matrix metalloproteinase inhibitors 22–26 . However, it is also critical to determine the factors influencing the selection of ABC.…”

Doxorubicin-induced cardiomyopathy: TERT gets to the heart of the matter

“…Administration of doxorubicin can lead to both short-and long-term cardiotoxic effects, ranging from subclinical alterations of myocardial structure and function to severe cardiomyopathy and heart failure that may result in heart transplantation or death. In this issue of Molecular Therapy, Chatterjee et al 1 address this key challenge in cardio-oncology by demonstrating that AAV9mediated gene transfer of murine telomerase reverse transcriptase (Tert) under control of the cardiomyocyte-specific cardiac troponin T promoter (AAV9-Tert) prevents cardiac atrophy and systolic dysfunction in a murine model of chronic doxorubicin cardiotoxicity. Doxorubicin is a potent cytotoxic antibiotic originally isolated from Streptomyces peucetius caesius and belongs to the anthracycline group of chemotherapeutic agents.…”

“…At the microscopic level, Chatterjee et al 1 show that AAV9-Tert gene transfer completely blocked the doxorubicin-induced cardiomyocyte atrophy and apoptosis in the myocardium, rescued severe misalignment of the sarcomeres upon doxorubicin treatment, and counteracted increased mitochondrial fission induced by doxorubicin. 1 Furthermore, the authors generated human cardiomyocytes from induced pluripotent stem cells (hiPSC -CMs) based on a differentiation protocol that included a selection step as well as a 60-day maturation period. Neither human TERT mRNA expression nor detectable telomerase activity was present in these differentiated hiPSC-CMs.…”

“…The effect of AAV9-Tert gene transfer on chronic doxorubicin cardiotoxicity in vivo and of AAV6-TERT gene transfer on acute doxorubicin toxicity in hiPSC-CMs in vitro was independent of the canonical function of telomerase since telomere length was unaltered. 1 TERT has multiple non-canonical roles that are independent of its telomere elongation activity and include signal transduction, gene expression regulation, and protection against oxidative damage. Under stress conditions, TERT is exported out of the nucleus and imported into mitochondria, where it may exert protective effects.…”