Doxorubicin‐induced Cardiomyopathy in the giant danio is associated with Apoptosis, Inflammation, and Collagen Accumulation

Abstract

Doxorubicin (Dox), an antineoplastic anthracycline used in the treatment of childhood leukemia, is associated with late‐onset cardiomyopathy. The mechanisms of Dox‐induced cardiac dysfunction are an area of intense investigations. Using light and transmission electron microscopy (TEM), we studied the effects of Dox on the heart of giant danio (GD), a small fish closely related to zebrafish. We compared short‐term high‐dose to long‐term low‐dose effects of Dox administrations. We found that short‐term (4 days) high‐dose Dox induced little inflammation or collagen accumulation in the GD myocardium. By contrast long‐term (4 weeks) low‐dose Dox induced apoptosis (TUNEL, TEM) and inflammation (MPO, TEM) in the ventricular myocardium. The number of MPO‐positive cells increased by 2 folds and 4 folds in Dox‐treated hearts, at 1 and 4 weeks respectively, with cell cycle activity (Edu) in cardiac myocytes (CM) and increased fibrosis (Trichrome, TEM). Interestingly, we found a spatially‐restricted pattern of fibrosis in the compact heart (CH). Consistent with this finding we observed by TEM that activated fibroblasts in the CH contributed to collagen accumulation. This data suggests that, except for marked cell cycle activation in CM, the GD heart response to Dox treatment appears analogous to that of human. Thus the GD may serve as an important model for the study of Dox‐induced cardiomyopathy.Grant Funding Source: FDC