Abstract 15483: Mitoquinone Pretreatment Mitigates Dox-induced Systolic Dysfunction in Isolated Rat Hearts

Abstract

Background: Doxorubicin (DOX) is a common and effective chemotherapeutic agent that can exert cardiotoxicity by inducing oxidative stress in mitochondria, compromising mitochondrial function, and inducing apoptosis. Currently, there is no treatment that targets this mechanism. We previously found that pretreatment with higher concentrations of mitoquinone (MQ), a mitochondrial antioxidant, exerts cardioprotection against DOX in myoblast H9C2 cells. Hypothesis: We hypothesize that MQ pretreatment would preserve cardiac function against DOX in isolated rat hearts. Methods: Cardiac parameters (heart rate (HR) and left ventricular end systolic pressure (LVESP)) were monitored before and after 60 min infusion of DOX, MQ, or DOX with MQ pretreatment (10-15 min) in a Langendorff preparation of male SD rat hearts. TUNEL assay was conducted on heart tissue slides to evaluate apoptosis. The ratio between the final and initial cardiac parameters was calculated and compared among experimental groups. Results: Higher dose DOX (25 μM, n=5) induced a higher reduction in the ratios of LVESP, to 39±5% than lower dose DOX infusion (20 μM, n=3; 74±3%). DOX had no effects on HR. A 60-minute perfusion of higher doses of MQ (1-5 μM, n=7) unexpectedly reduced the ratios of LVESP and HR to 73±12% and 66±5%, respectively. Higher dose MQ (1-2.5 μM, n=6) pretreatment showed similar improvement of LVESP ratio (68±9%) to lower dose MQ (0.25-0.5 μM, n=6; 71±11%). TUNEL assay showed that higher dose DOX caused a higher rate of apoptosis (number of TUNEL-positive nuclei) (326.3±6.4. n=3) than lower dose (214±29.5, n=3). Pretreatment with higher dose MQ prior to DOX 25 μM infusion resulted in a notable reduction of apoptosis (60.3±5, n=6) compared to DOX alone, while lower dose pretreatment reduced apoptosis to 70.5± 0.5 (n=4). Conclusion: This study suggests that infusion of DOX into the heart acutely attenuated cardiac systolic function accompanied with higher apoptotic cell damage. Although prolonged administration of higher doses of MQ suppressed cardiac function, MQ pretreatment for 10-15 minutes mitigated DOX-induced systolic dysfunction and reduced cardiomyocyte apoptosis. In summary, MQ pretreatment may mitigate DOX-induced cardiac damage.