Antioxidant therapy attenuates myocardial telomerase activity reduction in superoxide dismutase-deficient mice

Oxidative stress plays a pathological role in the development of heart failure. This study examined telomere biology in heart/muscle-specific manganese superoxide dismutase-deficient mice (H/M-SOD2−/−), which develop progressive congestive heart failure and exhibit pathology typical of dilated cardiomyopathy. EUK-8 (25 mg/kg/day), a superoxide dismutase and catalase mimetic, was administered to H/M-SOD2−/− mice for four weeks beginning at 8 weeks of age. Telomere length, telomerase activity, telomere-associated proteins, and cell death signals were assessed in hearts from control wild-type mice (H/M-Sod2 lox/ lox) and H/M-SOD2−/− mice either treated or untreated with EUK-8. While cardiac function was unchanged in these experimental mice, the end-diastolic dimension in H/M-SOD2−/− mice was notably dilated and could be significantly reduced by EUK-8 treatment. At the end of the study, no shortening of telomere length was observed in heart tissues from all mice tested, but telomerase activity was decreased in heart tissue from H/M-SOD2−/− mice compared to control mice. Protein expression for telomerase reverse transcriptase and telomere repeat binding factor 2 was also downregulated in H/M-SOD2−/− heart tissue as was expression of phospho-Akt, insulin-like growth factor, and endothelial nitric oxide synthase. Expression levels of Sirt1, a lifespan modulator, were enhanced while FoxO3a was depressed in H/M-SOD2−/− hearts. All of the changes seen in H/M-SOD2−/− heart tissue could be inhibited by EUK-8 treatment. Taken together, the results suggest that oxidant stress might affect myocardial telomerase activity and telomere-associated proteins. Telomerase may therefore play a pivotal role in antioxidant defense mechanisms, and may be useful as a novel therapeutic tool for treating human heart failure.

Research Highlights► Telomerase activity plays a pivotal role as an antioxidant defense mechanism. ► Antioxidant Euk-8 prevents the dilatation of LV diastolic diameter in MnSOD-knockout mice. ► Antioxidant therapy may be useful for the treatment of human heart failure.