Abstract 352: Juvenile Doxorubicin Treatment Impairs Recovery and Promotes Apoptosis in Adult Hearts via failure of up-regulation of Mcl-1 after Myocardial Infarction
The anthracycline doxorubicin (DOX) is an effective chemotherapeutic agent used to treat pediatric cancers. However, it is associated with cardiotoxicity which can manifest many years after the initial exposure. Very little is known about the mechanisms of this late-onset cardiotoxicity. To understand this problem, we have developed a model of pediatric DOX cardiotoxicity where mouse pups were injected with 4 low doses of DOX or saline at 5, 10, 15, and 20 days of age. After completion of treatment, all mice were healthy and had normal cardiac function as adults. However, when mice were subjected to myocardial infarction (MI), DOX treated mice developed severe cardiac fibrosis and had increased mortality compared to saline treated mice (67% vs. 20%), suggesting that these hearts do not tolerate stress well. Assessment of infarct size revealed that infarct size was greater in DOX-treated hearts compared to saline. Anthracyclines are known to affect the Bcl-2 family proteins which are also important regulators of cell death in the heart. We found that Mcl-1, an anti-apoptotic Bcl-2 protein, is expressed in the heart and localizes to the mitochondria. Overexpression of Mcl-1 in HL-1 myocytes reduced simulated I/R-mediated cell death (58±8% vs. 26±7%, n=3, p<0.05), suggesting that Mcl-1 promotes survival of cardiac cells in response to stress. Immunostaining analysis of Mcl-1 expression in mouse hearts revealed that Mcl-1 was significantly increased in myocytes in the border zone after acute MI. Myocytes with enhanced Mcl-1 expression were negative for apoptosis as assessed by TUNEL staining, whereas cells with reduced Mcl-1 expression were TUNEL positive. Since anthracyclines have been shown to reduce Mcl-1 expression in cancer cells, we investigated whether juvenile DOX treatment would suppress Mcl-1 expression in adult heart in response to stress. We found that cardiac myocytes in the border zone of DOX treated hearts failed to upregulate Mcl-1 in response to MI which likely impaired recovery and contributed to increased injury and mortality. These studies suggest upregulation of Mcl-1 is an important salvage response after MI and that juvenile DOX treatment affects Mcl-1 expression in adulthood resulting in a heart that is more susceptible to stress.
This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).