odeling Associated with Doxorubicin Chemotherapy

Downlo orubicin is a highly effective cancer treatment whose use is severely limited by dose-dependent cardiity. It is well established that doxorubicin increases reactive oxygen species (ROS) production. In this we investigated contributions to doxorubicin cardiotoxicity from Nox2 NADPH oxidase, an important ource in cardiac cells, which is known to modulate several key processes underlying the myocardial se to injury. Nox2-deficient mice (Nox2) and wild-type (WT) controls were injected with doxorubicin g/kg) or vehicle and studied 8 weeks later. Echocardiography indicated that doxorubicin-induced cone dysfunction was attenuated in Nox2 versus WT mice (fractional shortening: 29.5 ± 1.4 versus 25.7 ± P < 0.05). Similarly, in vivo pressure-volume analysis revealed that systolic and diastolic function was ved in doxorubicin-treated Nox2 versus WT mice (ejection fraction: 52.6 ± 2.5 versus 28.5 ± 2.3%, dtmin: −8,379 ± 416 versus −5,198 ± 527 mmHg s; end-diastolic pressure-volume relation: 0.051 ± versus 0.114 ± 0.012; P < 0.001). Furthermore, in response to doxorubicin, Nox2 mice exhibited less rdial atrophy, cardiomyocyte apoptosis, and interstitial fibrosis, together with reduced increases in proc gene expression (procollagen IIIαI, transforming growth factor-β3, and connective tissue growth facnd matrix metalloproteinase-9 activity, versus WT controls. These alterations were associated with cial changes in NADPH oxidase activity, oxidative/nitrosative stress, and inflammatory cell infiltration. und that adverse effects of doxorubicin were attenuated by acute or chronic treatment with the AT1 or antagonist losartan, which is commonly used to reduce blood pressure. Our findings suggest that ROS ically derived from Nox2 NADPH oxidase make a substantial contribution to several key processes specif underlying development of cardiac contractile dysfunction and remodeling associated with doxorubicin chemotherapy. Cancer Res; 70(22); 9287–97. ©2010 AACR.