Infiltrating macrophages amplify doxorubicin-induced cardiac damage: role of catecholamines
Jessica Gambardella, Gaetano Santulli, Antonella Fiordelisi, Federica Andrea Cerasuolo, Xujun Wang, Nella Prevete, Eduardo Sommella, Roberta Avvisato, Antonietta Buonaiuto, Giovanna Giuseppina Altobelli, Laura Rinaldi, Francesco Chiuso, Antonio Feliciello, Fabrizio Dal Piaz, Pietro Campiglia, Michele Ciccarelli, Carmine Morisco, Junichi Sadoshima, Guido Iaccarino, Daniela Sorriento
Abstract
BACKGROUND: The functional contribution of non-myocyte cardiac cells, such as inflammatory cells, in the setup of heart failure in response to doxorubicin (Dox) is recently becoming of growing interest. OBJECTIVES: The study aims to evaluate the role of macrophages in cardiac damage elicited by Dox treatment. METHODS: C57BL/6 mice were treated with one intraperitoneal injection of Dox (20 mg/kg) and followed up for 5 days by cardiac ultrasounds (CUS), histological, and flow cytometry evaluations. We also tested the impact of Dox in macrophage-depleted mice. Rat cardiomyoblasts were directly treated with Dox (D-Dox) or with a conditioned medium from cultured murine macrophages treated with Dox (M-Dox). RESULTS: In response to Dox, macrophage infiltration preceded cardiac damage. Macrophage depletion prevents Dox-induced damage, suggesting a key role of these cells in promoting cardiotoxicity. To evaluate the crosstalk between macrophages and cardiac cells in response to DOX, we compared the effects of D-Dox and M-Dox in vitro. Cell vitality was lower in cardiomyoblasts and apoptosis was higher in response to M-Dox compared with D-Dox. These events were linked to p53-induced mitochondria morphology, function, and autophagy alterations. We identify a mechanistic role of catecholamines released by Dox-activated macrophages that lead to mitochondrial apoptosis of cardiac cells through β-AR stimulation. CONCLUSIONS: Our data indicate that crosstalk between macrophages and cardiac cells participates in cardiac damage in response to Dox.