心脏毒性是蒽环类药物治疗的主要并发症，严重影响预后。目前缺乏有效的药物治疗蒽环类药物诱导的心肌病（AICM）。中性粒细胞来源的酶过氧化物酶（MPO）在人体内升高的血浆水平预示着AICM的发生。我们假设MPO的释放在AICM的发生中起到了直接的作用。将静脉注射蒽环类药物阿霉素（DOX）的小鼠，与生理盐水（NaCl）处理的对照组相比，循环血液和心脏组织中出现更高的中性粒细胞计数和MPO水平。类似中性粒细胞的HL-60细胞在受到DOX刺激后释放的MPO明显增加。DOX引起心脏组织的大量亚硝酸化应激，并使野生型小鼠的肌纤维蛋白卡那酰化增加，而Mpo-/-小鼠中未见这种现象。相应地，DOX和MPO共同处理的人诱导多能干细胞来源的心肌细胞（hiPSC-CMs），与单独DOX处理相比，加重了hiPSC-CM的收缩能力丧失。DOX处理的动物出现明显的心脏细胞凋亡和炎症，而在缺乏MPO的动物中得到减轻。最后，基因缺失的MPO和药物抑制MPO保护小鼠不发生AICM的发展。DOX的抗癌疗效不受MPO缺失的影响。在本研究中，我们确定MPO是AICM的关键介质。我们证明DOX导致心脏中性粒细胞浸润和MPO释放，通过促进肌纤维蛋白氧化、心脏炎症和心肌细胞凋亡而直接损害心脏收缩能力。因此，MPO成为预防AICM的有前途的药物靶点。© 2023年，施普林格-费尔拉格德国公司，施普林格自然出版集团的一部分。

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.© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.