Myeloperoxidase is a critical mediator of anthracycline-induced cardiomyopathy
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Published:2023-09-01
Issue:1
Volume:118
Page:
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ISSN:1435-1803
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Container-title:Basic Research in Cardiology
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language:en
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Short-container-title:Basic Res Cardiol
Author:
Nettersheim Felix SebastianORCID, Schlüter Johannes David, Kreuzberg Wiebke, Mehrkens Dennis, Grimm Simon, Nemade Harshal, Braumann Simon, Hof Alexander, Guthoff Henning, Peters Vera, Hoyer Friedrich Felix, Kargapolova Yulia, Lackmann Jan-Wilm, Müller Stefan, Pallasch Christian P., Hallek Michael, Sachinidis Agapios, Adam Matti, Winkels Holger, Baldus Stephan, Geißen Simon, Mollenhauer Martin
Abstract
AbstractCardiotoxicity 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.
Funder
Deutsche Forschungsgemeinschaft Neven-DuMont Foundation Center for Molecular Medicine Cologne, University of Cologne Koeln Fortune Program Universitätsklinikum Köln
Publisher
Springer Science and Business Media LLC
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology
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