Myeloperoxidase is a critical mediator of anthracycline-induced cardiomyopathy.

IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Felix Sebastian Nettersheim, Johannes David Schlüter, Wiebke Kreuzberg, Dennis Mehrkens, Simon Grimm, Harshal Nemade, Simon Braumann, Alexander Hof, Henning Guthoff, Vera Peters, Friedrich Felix Hoyer, Yulia Kargapolova, Jan-Wilm Lackmann, Stefan Müller, Christian P Pallasch, Michael Hallek, Agapios Sachinidis, Matti Adam, Holger Winkels, Stephan Baldus, Simon Geißen, Martin Mollenhauer
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引用次数: 0

Abstract

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.

Abstract Image

髓过氧化物酶是蒽环类药物诱导的心肌病的关键介质。
心脏毒性是蒽环类药物治疗的主要并发症,对预后有负面影响。目前缺乏有效的药物治疗来预防蒽环类药物诱导的心肌病(AICM)。中性粒细胞来源的髓过氧化物酶(MPO)的血浆水平升高可预测人类AICM的发生。我们假设MPO的释放是AICM的原因之一。与生理盐水(NaCl)处理的对照组相比,静脉注射蒽环类药物阿霉素(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了心脏组织中广泛的亚硝化应激,同时增加了肌块蛋白的羰基化,但在Mpo-/-小鼠中没有。因此,与单独DOX治疗相比,用DOX和MPO联合治疗人诱导多能干细胞衍生的心肌细胞(hiPSC CM)加重了hiPSC CM收缩性的丧失。DOX处理的动物表现出明显的心脏细胞凋亡和炎症,这在MPO缺乏的动物中减弱。最后,遗传性MPO缺乏和药理学MPO抑制保护小鼠免受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的关键介质。我们证明DOX诱导心脏中性粒细胞浸润和MPO的释放,MPO通过促进肌块蛋白的氧化、心脏炎症和心肌细胞凋亡直接损害心脏收缩性。MPO因此成为预防AICM的一个有前景的药理学靶点。
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来源期刊
Basic Research in Cardiology
Basic Research in Cardiology 医学-心血管系统
CiteScore
16.30
自引率
5.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Basic Research in Cardiology is an international journal for cardiovascular research. It provides a forum for original and review articles related to experimental cardiology that meet its stringent scientific standards. Basic Research in Cardiology regularly receives articles from the fields of - Molecular and Cellular Biology - Biochemistry - Biophysics - Pharmacology - Physiology and Pathology - Clinical Cardiology
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