Cardiac resident macrophage affects doxorubicin-induced cardiomyopathy

Abstract

Abstract Doxorubicin is an anticancer drug commonly used in patient with lymphoma or breast cancer, and its main side effect is cardiotoxicity by damaging cardiomyocytes. While the mecahnisms of doxorubicin-induced cardiotoxicity are poorly understood. Recent studies demonstrated that the cardiac resident macrophages play essential roles in regulating homeostasis of cardiomyocyte, promoting electrical conduction, and eliminating dead cardiomyocytes and debris. In this study, we showed that cardiac resident macrophages were involved in cardiomyocyte death in a mouse model of doxorubicin-induced cardiotoxicity. Mice were injected with 20 mg/kg of doxorubicin and their hearts were harvested to determine the composition of immune cells in the heart. Using FACS analysis, we observed that the number of CD45+Ly6GintCD11b+F4/80+ macrophages per mg was significantly reduced in the hearts of doxorubicin-injected mice. These cells are cardiac resident macrophages with a CCR2- MHCⅡ+ phenotype. Also, The TUNEL assay confirmed that macrophage death observed in the cardiac tissue of mice 1 day following doxorubicin administration. Finally, we treated iPSC-derived cardiomyocytes and macrophages with doxorubicin and observed cell death, and found that macrophages were more sensitive to doxorubicin than cardiomyocytes. These results suggest that cardiac resident macrophages are sensitive to doxorubicin, which can affect the death of neighboring cardiomyocytes and lead to cardiotoxicity.