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    The effects of mitoquinone pretreatment on doxorubicin-induced acute cardiac dysfunction

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    Introduction: Doxorubicin (DOX) is a widely used anti-cancer drug notorious for its irreversible cardiac toxicity. Currently, Dexrazoxane is the only FDA-approved treatment for this toxicity. However, Dexrazoxane still bears some serious adverse events, and developing new strategies to mitigate DOX-induced heart damage is critical. Our lab has shown that pretreatment of the H9c2 myoblast cells with mitoquinone (MitoQ), a mitochondrial-targeted antioxidant, and significantly improved cells’ resiliency to DOX. This study aimed to determine if MitoQ pretreatment can preserve cardiac function against DOX-induced damage in isolated rat hearts. Objectives: The effects of DOX and MitoQ on cardiac function were evaluated in isolated rat hearts. Moreover, the benefits of MitoQ pretreatment on DOX-induced cardiac dysfunction were also assessed. Methods: Langendorff heart preparation was performed after anesthesia of male SD rats (275-325 g). Hearts were isolated and retrograde perfused with Krebs’ buffer at a constant pressure of 80 mmHg with 37 ⁰C and pH of 7.35-7.45. Cardiac parameters, including left ventricle end-systolic pressure (LVESP), left ventricle end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDP=LVESP-LVEDP), maximal rate of rise of LVP (dP/dt(max)), and heart rate (HR), were measured by a pressure transducer placed in the left ventricle of the rat heart. After obtaining a stable initial cardiac function, DOX (20 µM or 25 µM) or MitoQ (0.1-0.5 or 1-2.5 µM) were infused into the heart for 60 min. to determine the individual drug\u27s effects on the cardiac function. Moreover, another set of hearts was pretreated with MitoQ (0.25-0.5 or 1-2.5 µM) for 10-15 min before giving DOX (25 µM) to evaluate if MitoQ pretreatment would mitigate DOX-induced cardiac dysfunction. Cardiac functions were recorded every 5 min. throughout the experiments. The ratio between the final and initial recordings was calculated and compared among experimental groups. Results: Acute infusion of DOX into the isolated hearts dose-dependently reduced some cardiac parameters. Higher dose DOX (25 μM, n=5) induced a higher reduction in the ratios of LVESP, LVDP, and dP/dt(max) to 0.39±0.05, 0.35±0.06, and 0.26±0.05 than those of lower dose DOX infusion (20 μM, n=2; 0.77±0.01, 0.75±0.01, and 0.57±0.01), respectively. DOX had no effects on LVEDP and HR. Moreover, lower doses of MitoQ (0.1-0.5 μM, n=6) only slightly reduced HR to 0.77±0.01 without affecting other parameters. By contrast, higher doses of MitoQ (1-5 μM, n=4) reduced the ratios of LVESP, LVDP, dP/dt(max), and HR to 0.72±0.12, 0.51±0.18, and 0.45±0.17 0.65±0.07, respectively. Interestingly, MitoQ pretreatment before DOX (25 µM) exhibited better cardiac function accompanied by reduced HR than DOX alone. Higher MitoQ (1-2.5 µM) pretreatment improved the ratios of cardiac LVESP, LVDP, and dP/dt(max) to 0.67±0.14, 0.65±0.16, and 0.40±0.09, which were higher than those of lower dose MitoQ (0.25-0.5 μM, n=3; 0.49±0.11, 0.44±0.11, and 0.36±0.08), respectively. Conclusion: The preliminary data suggest that infusion of DOX into the heart acutely attenuated cardiac systolic function. Higher doses of MitoQ, not lower doses, also suppressed cardiac function. MitoQ pretreatment mitigated DOX-induced heart dysfunction. Acknowledgement: The project is funded by CCDA at PCOM
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