Myeloperoxidase is a critical mediator of anthracycline-induced cardiomyopathy

• DOI: 10.1007/s00395-023-01006-0
• Publication Date: 2023-09-01T11:04:26Z
• Authors: Felix Sebastian N...; Johannes David Sc...; Wiebke Kreuzberg; Dennis Mehrkens; Simon Grimm; Harshal Nemade; Simon Braumann; Alexander Hof; Henning Guthoff; Vera Peters; Friedrich Felix H...; Yulia Kargapolova; Jan-Wilm Lackmann; Stefan Müller; Christian P. Pall...; Michael Hallek; Agapios Sachinidis; Matti Adam; Holger Winkels; Stephan Baldus; Simon Geißen; Martin Mollenhauer
• Keywords: Contractility; Cardiotoxicity

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