Cardiotoxicity is a major complication of anthracycline therapy that negatively impacts prognosis. Effective pharmacotherapies for prevention of anthracycline-induced cardiomyopathy (AICM) are currently lacking. Increased plasma levels of the neutrophil-derived enzyme myeloperoxidase (MPO) predict occurrence of AICM in humans. We hypothesized that MPO release causally contributes to AICM. Mice intravenously injected with the anthracycline doxorubicin (DOX) exhibited higher neutrophil counts and MPO levels in the circulation and cardiac tissue compared to saline (NaCl)-treated controls. Neutrophil-like HL-60 cells exhibited increased MPO release upon exposition to DOX. DOX induced extensive nitrosative stress in cardiac tissue alongside with increased carbonylation of sarcomeric proteins in wildtype but not in Mpo^−/− mice. Accordingly, co-treatment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with DOX and MPO aggravated loss of hiPSC-CM-contractility compared to DOX treatment alone. DOX-treated animals exhibited pronounced cardiac apoptosis and inflammation, which was attenuated in MPO-deficient animals. Finally, genetic MPO deficiency and pharmacological MPO inhibition protected mice from the development of AICM. The anticancer efficacy of DOX was unaffected by MPO deficiency. Herein we identify MPO as a critical mediator of AICM. We demonstrate that DOX induces cardiac neutrophil infiltration and release of MPO, which directly impairs cardiac contractility through promoting oxidation of sarcomeric proteins, cardiac inflammation and cardiomyocyte apoptosis. MPO thus emerges as a promising pharmacological target for prevention of AICM.

心脏毒性是蒽环类药物治疗的主要并发症，会对预后产生负面影响。目前缺乏预防蒽环类药物诱发的心肌病（AICM）的有效药物疗法。中性粒细胞衍生酶髓过氧化物酶 (MPO) 的血浆水平升高可预测人类 AICM 的发生。我们假设 MPO 释放对 AICM 有因果影响。与盐水 (NaCl) 处理的对照组相比，静脉注射蒽环类阿霉素 (DOX) 的小鼠在循环和心脏组织中表现出更高的中性粒细胞计数和 MPO 水平。中性粒细胞样 HL-60 细胞在暴露于 DOX 后表现出 MPO 释放增加。 DOX 在野生型小鼠中诱导心脏组织中广泛的亚硝化应激，同时增加肌节蛋白的羰基化，但在Mpo ^−/−小鼠中则不然。因此，与单独使用 DOX 治疗相比，用 DOX 和 MPO 共同治疗人诱导多能干细胞来源的心肌细胞 (hiPSC-CM) 会加剧 hiPSC-CM 收缩性的丧失。 DOX 治疗的动物表现出明显的心脏细胞凋亡和炎症，而在 MPO 缺陷的动物中，这种情况减弱。最后，遗传性 MPO 缺陷和药理 MPO 抑制可保护小鼠免受 AICM 的发展。 DOX 的抗癌功效不受 MPO 缺乏的影响。在此，我们将 MPO 确定为 AICM 的关键调解者。我们证明 DOX 诱导心脏中性粒细胞浸润和 MPO 释放，通过促进肌节蛋白氧化、心脏炎症和心肌细胞凋亡直接损害心肌收缩力。因此，MPO 成为预防 AICM 的有前途的药理学靶点。