Evaluation of the effects of mitoquinone on doxorubicin-induced acute cardiac damage

Background: Doxorubicin (DOX)-induced cardiotoxicity remains a high priority to overcome due to irreversibility and lack of abundant preventions. DOX damages the heart tissue principally by overproduction of mitochondrial superoxide and intercalation with the topoisomerase II in the nucleus. Ultimately, cardiac cells become apoptotic, and heart function declines. Our lab has shown that Mitoquinone (MQ), a mitochondria-targeted antioxidant, improves H9c2 cell viability in the presence of DOX. We hypothesize that MQ would counteract DOX to preserve cardiac cells and function in isolated rat hearts, possibly by reducing mitochondrial superoxide production and intracellular accumulation. Methods: H9c2 cells (passages < 18) were incubated with DOX (40 [micro]M) with or without MQ (0.005 [mu]M - 5 [mu]M) for 24 hours before measuring mitochondrial superoxide anion levels and DOX intracellular accumulation. Furthermore, heart rate (HR) and left ventricular endsystolic pressure (LVESP) were recorded before and after a 60-minute infusion of DOX or DOX with MQ in isolated rat hearts. TUNEL staining was performed on heart tissue slides to assess apoptosis. All the data was expressed as a ratio between treatment and DOX alone or between final to initial values. Statistical significance was evaluated using ANOVA with Student Newman Keuls post-hoc analysis. Results: Hearts perfused with DOX (25 [micro]M, n = 5) displayed lower final LVESP with 39 +/- 5% of the initial baseline. By contrast, hearts treated with 0.25 [micro]M MQ (n = 4) or 1 [micro]M MQ (n = 5) manifested exhibited a higher final LVESP to 44 +/- 8% and 90 +/- 6% of initial baselines, respectively. Additionally, MQ administration significantly reduced cardiac cell apoptosis to 8 +/- 1% (0.25 [micro]M, n = 2) and 6 +/- 1% (1 [micro]M, n = 5, p < 0.05) when compared to DOX (88 +/- 2%, n = 4). In contrast to DOX, MQ (1 [micro]M, n = 4) showed 27 +/- 9% (n = 4) reduction in mitochondrial superoxide levels and 54 +/- 6% (n = 6, p < 0.05) less intracellular DOX deposition in H9c2 cells. Conclusion: This study suggests acute DOX administration to the heart severely compromises cardiac systolic function with higher induction of cell apoptosis. MQ exerts cardio-protection with higher systolic function and cell viability by attenuating mitochondrial superoxide levels and intracellular DOX accumulation.