Abstract 16027: Mitochondrial ATP-Binding Cassette Protein-1 (mABC1) Protects Against Doxorubicin-Mediated Cardiotoxicity
Background: Doxorubicin (DOX) is an anticancer drug that causes cardiomyopathy through iron-mediated oxygen radical damage. We had previously shown that mitochondrial ATP-biding cassette protein-1 (mABC1) plays a role in mitochondrial iron homeostasis and export, and its genetic deletion leads to cardiomyopathy with mitochondrial iron accumulation. We hypothesized that a reduction in mitochondrial iron levels through mABC1 overexpression would attenuate the cardiotoxic effects of DOX.
Results: DOX treatment of neonatal rat cardiomyocytes (NRCM) downregulated mABC1 and resulted in accumulation of mitochondrial iron and DOX. Furthermore, mABC1 overexpression exerted protective effects against DOX in NRCM. To confirm the in vitro data, we generated cardiac-specific mABC1 transgenic (TG) mice. Treatment with multiple intraperitoneal injections of DOX resulted in a significant decrease in cardiac systolic function as well as disruption of mitochondrial morphology in non-transgenic (NTG) mice, while mABC1 TG mice displayed preserved cardiac function and mitochondrial morphology. Tissue lipid peroxidation (a marker of cellular oxidative stress) was increased in NTG mice compared to mABC1 TG, while cardiac mitochondrial DNA content and mRNA levels of key regulators of mitochondrial biogenesis were decreased. Although the number of TUNEL-positive apoptotic cardiomyocytes was comparable, NTG mice hearts showed higher levels of microtubule-associated protein light chain 3 form 2 (LC3-II) and beclin-1, suggesting higher autophagic flux compared to mABC1 TG mice. To further test the hypothesis that iron homeostasis is involved in DOX cardiotoxicity, we treated mice with dexrazoxane (a unique iron chelator that has been shown in clinical settings to prevent DOX cardiotoxicity) in the presence and absence of DOX. Treatment with dexrazoxane suppressed mitochondrial iron accumulation and prevented toxicity by DOX.
Conclusions: These results suggest that the cardiotoxic effects of DOX are through mitochondrial iron accumulation, impairment of mitochondrial integrity and higher autophagy flux. Furthermore, mABC1 and dexrazoxane protect against DOX-induced cardiomyopathy by attenuating mitochondrial iron accumulation.
- © 2011 by American Heart Association, Inc.