Mitochondrial Telomerase Prevents Chemotherapy‐Induced Cardiovascular Toxicity

Abstract

Anti‐cancer therapy (including doxorubicin (Dox)) is frequently used to combat growth of tumors. Chemotherapy (CTx) induced cardiotoxicity manifests as cardiomyopathy and can ultimately progress to heart failure and significantly contributes to morbidity and mortality among cancer survivors. Limited evidence demonstrates the impact of Dox on vascular endothelial function and possible contribution to progression of heart failure. TERT, the catalytic subunit of telomerase, has been increasingly recognized for its benificial effects on vascular quiescence via suppression of mitochondrial ROS to maintain mitochondrial integrity. Anthracycline treatment (e.g., Dox) correlates with both, suppressed TERT expression and activity as well as increased mitochondrial DNA damage. These combined effects of inadequate TERT levels and loss of mitochondrial integrity may contribute to CTx induced cardiotoxicity.The goal of this study was to define the contribution of TERT to CTx‐induced endothelial dysfunction and to cardiac dysfunction. We hypothesize that TERT gain of function prevents, while TERT loss of function augments CTx‐induced microvascular and cardiac dysfunction. We modulated TERT activation with a known telomerase activator cycloastragenol (CAG) via dietary supplement.In TERT WT animals, treatment with Dox significantly reduced endothelial dependent dilator function as early as two weeks after first dose. Dietary supplementation with CAG prevented Dox induced decrease in endothelial function (A). In contrast, in TERT‐specific KO animals Dox induced vascular damage was increased and CAG treatment failed to prevent endothelial dysfunction (B). Cardiac function followed similar patterns. In WT rats Dox caused significant reductions in left ventricular ejection fraction (LVEF) six weeks after the first dose of Dox, which was prevented by dietary supplementation with CAG. The reduction in LVEF was augmented in TERT KO animals and not rescued by CAG (C). Collectively, our data showed that Dox induced endothelial dysfunction was prevented by the pharmacological activation of TERT via CAG and furthermore suggests, that Dox induced endothelial dysfunction manifests before or independent of a cardiac damage. Likewise, CAG administration was sufficient to prevent reductions in LVEF relative to baseline in Dox treated WT animals. Specificity of a TERT mediated phenotype via CAG was established by failure of rescue in TERT KO rats. Ultimately, our results indicate that CAG has the potential as therapeutic to counteract the detrimental effects of CTx in the cardiovascular system via activation of TERT.