Abstract 9380: Rescuing Mitochondrial Fusion/Fission Balance Mitigates Oxidative Stress, Myocardial Injury and Apoptosis in Rats with Doxorubicin-induced Cardiotoxicity

Abstract

Introduction: Doxorubicin (DOX) has been an extensively used chemotherapeutic drug in handling a wide range of cancers. Cardiotoxicity induced by DOX is a serious adverse effect of oncologic therapy. Although mitochondrial dynamic modulators including mitochondrial fission inhibitor (Mdivi-1) and fusion promoter (M1) have been shown as potential therapeutic remedies to treat various cardiovascular disorders, the cardioprotective effects of Mdivi-1 and M1 in DOX-induced cardiotoxicity is not known. Hypothesis: Mdivi-1 and M1 treatments reduce oxidative stress, myocardial injury, and programmed cell death by apoptosis, leading to improved left ventricular (LV) function in rats with DOX-induced cardiotoxicity. Methods: Male Wistar rats (n=20) were injected with either DOX (3 mg/kg, 6 doses, n=5) or 3% DMSO in NSS (n=5) as a control. In the DOX group, DOX-treated rats were received one of the following treatments: 1) 3% DMSO in NSS (n=5), 2) Mdivi-1 (1.2 mg/kg/day, n=5), 3) M1 (2 mg/kg/day, n=5). All treatments were given to the rats via intraperitoneal injection for 30 days beginning simultaneously with the first DOX injection. LV function, cardiac tissue malondialdehyde (MDA), serum cardiac troponin-I (c-TnI), and cleaved caspase-3 (CC3) protein levels were determined. Results: Injection of DOX markedly increased cardiac MDA, c-TnI, and CC3 levels (Fig. 1A-D). Impaired left ventricular ejection fraction (67% for DOX vs. 91% for control) was observed. Mdivi-1 and M1 co-treatment remarkably reduced the levels of MDA, c-TnI, and CC3, leading to increased LVEF from 67% in DOX to 89% in Mdivi-1 and 90% in M1, respectively (Fig. 1A-D). Conclusions: Mitochondrial fission inhibitor and fusion promoter effectively protected the heart from DOX-induced cardiotoxicity through suppression of oxidative stress, myocardial injury, and apoptosis. These findings indicate the mitochondrial dynamics as novel therapeutic targets in preventing Dox-induced cardiotoxicity.