Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
Department of Medicine (Cardiology) and Department of Molecular Pharmacology, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Montefiore University Hospital, New York, USA.
Cell Mol Life Sci. 2023 Oct 11;80(11):323. doi: 10.1007/s00018-023-04922-5.
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.
The study aims to evaluate the role of macrophages in cardiac damage elicited by Dox treatment.
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).
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.
Our data indicate that crosstalk between macrophages and cardiac cells participates in cardiac damage in response to Dox.
非心肌细胞（如炎性细胞）在阿霉素（Dox）引发心力衰竭中的功能贡献，最近引起了越来越多的关注。
本研究旨在评估巨噬细胞在 Dox 治疗引起的心脏损伤中的作用。
C57BL/6 小鼠接受一次腹腔注射 Dox（20mg/kg），并用心脏超声（CUS）、组织学和流式细胞术进行 5 天的随访。我们还测试了 Dox 在巨噬细胞耗竭小鼠中的影响。将 Dox 直接作用于大鼠心肌细胞（D-Dox）或作用于经 Dox 处理的培养鼠巨噬细胞的条件培养基（M-Dox）。
在 Dox 作用下，巨噬细胞浸润先于心脏损伤。巨噬细胞耗竭可预防 Dox 诱导的损伤，表明这些细胞在促进心脏毒性方面具有关键作用。为了评估巨噬细胞与心脏细胞在 Dox 作用下的相互作用，我们比较了 D-Dox 和 M-Dox 在体外的作用。与 D-Dox 相比，心肌细胞活力更低，凋亡更高。这些事件与 p53 诱导的线粒体形态、功能和自噬改变有关。我们发现，Dox 激活的巨噬细胞释放的儿茶酚胺通过β-AR 刺激导致心脏细胞线粒体凋亡，从而发挥一种机制作用。
我们的数据表明，巨噬细胞和心脏细胞之间的相互作用参与了 Dox 引起的心脏损伤。
