Abstract 17890: Cardiomyocyte-Specific ATGL Over-Expression Prevents Doxorubicin-Induced Cardiac Dysfunction in Female Mice
Anthracyclines such as, doxorubicin (DOX) are an effective class of antineoplastic agents. Despite its efficacy in the treatment of a variety of cancers including breast cancer, the clinical use of DOX is limited by cardiac side effects. While it has been shown that DOX alters myocardial fatty acid metabolism, it is poorly understood whether variations in myocardial triacylglycerol (TG) metabolism contribute to DOX-induced cardiotoxicity. Since TG catabolism in the heart is primarily controlled by adipose triglyceride lipase (ATGL), this study examined the influence of DOX on cardiac ATGL expression and TG levels as well as the consequence of forced-expression of ATGL in the setting of DOX-induced cardiotoxicity. To do this, wild type (WT) mice and mice with cardiomyocyte-specific ATGL over-expression (MHC-ATGL) received weekly intraperitoneal injections of saline or DOX (8mg/kg) for four weeks. Heart rate, heart weight to tibia length ratio and DOX-induced body weight loss were comparable between genotypes. As expected, myocardial TG content was significantly reduced in MHC-ATGL mice compared to the WT following DOX treatment. Echocardiographic analysis also revealed a significant reduction of systolic heart function (% ejection fraction) in DOX-treated WT mice (saline, 54.6 ± 3.6 vs. DOX, 47.1 ± 1.0, p<0.05), an effect that was not observed in DOX-treated MHC-ATGL mice (saline, 58.7 ± 2.6 vs DOX, 57.2 ± 2.4, p = 0.7). The wet to dry lung weight ratio was increased in DOX-treated WT (saline, 10.1 ± 0.9 vs. DOX, 14.0 ± 1.0, p<0.05), but not MHC- ATGL mice (saline, 9.6 ± 0.6 vs. DOX, 10.9 ± 0.2, p = 0.12), suggesting a protection from pulmonary signs of heart failure. Surprisingly, the preservation of cardiac function in MHC-ATGL mice following DOX treatment was associated with decreased protein expression of PPARα, Oxpat, CD36, and FATP1 as well as increased phosphorylation of acetyl CoA carboxylase when compared to DOX-treated WT mice, indicating a reduction of fatty acid uptake and subsequent oxidation in the cardiomyocyte. Taken together, our data suggest that chronic reduction in myocardial TG content by cardiomyocyte-specific ATGL over-expression is able to prevent DOX-induced cardiac dysfunction.
- © 2011 by American Heart Association, Inc.