Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

MPO-mediated monocyte and macrophage migration in myocardial infarction

V. Peters1, I. Erdmann2, B. Arand2, F. Mathei1, D. Mehrkens2, S. Geißen1, D. Muders1, F. Nettersheim2, H. Hansen2, V. Rudolph3, A. Klinke3, H. Winkels2, M. Adam2, M. Torun1, S. Baldus4, M. Mollenhauer2, für die Studiengruppe: Experimentelle Kardiologie

1Klinik III für Innere Medizin - Experimentelle Kardiologie, Universitätsklinikum Köln, Köln; 2Klinik III für Innere Medizin, Herzzentrum der Universität zu Köln, Köln; 3Allgemeine und Interventionelle Kardiologie/Angiologie, Herz- und Diabeteszentrum NRW, Bad Oeynhausen; 4Klinik für Kardiologie, Angiologie, Pneumologie und Internistische Intensivmedizin, Herzzentrum der Universität zu Köln, Köln;

Background: Plasma levels of the polymorphonuclear neutrophil (PMN)-derived enzyme myeloperoxidase (MPO) correlate with prognosis and severity of myocardial infarction (MI). Apart from its capacity to catalyse the highly reactive oxygen species (ROS) hydrogen peroxide and generation of hypochlorous acid (HOCl), MPO attracts and activates PMN and monocytes, cells playing a crucial role in inflammation and tissue remodelling post MI. Purpose: Herein we evaluate the role of MPO on monocyte and macrophage activation, migration and infiltration in vitro and ex vivo, and extrapolate this using a murine model of MI. Methods and Results: To assess monocyte migration in vitro, THP-1 monocytes were incubated overnight with MPO (10ng/ml) in the presence H2O2. Real-time PCR analyses showed increased expression of chemokine receptors CCR2, CX3CR1 and CCR5 as compared to unstimulated cells, all playing a major role in monocyte recruitment after MI. By using Ibidi chemotaxis assays, we showed that MPO/ H2O2-treated cells migrate a larger distance in presence of the chemoattractant MCP-1 as compared to MPO only treated or untreated cells. In vivo, intraperitoneal injection of MPO (15 µg) in Mpo-/- mice resulted in a marked increase in peritoneal leukocyte recruitment compared to mice injected with saline. These leukocytes were subsequently identified as macrophages (F4/80+) by flow cytometry. Using a murine MI model of permanent ligation of the left descending coronary artery (LAD), we showed less monocyte and macrophage infiltration into the left ventricle in Mpo-/- mice one day after LAD ligation, whereas more remained in the spleen, the primary monocyte recruiting organ 1 day after MI. This was confirmed by both flow cytometry and immunohistochemistry, suggesting a role for MPO in monocyte/macrophage recruitment in MI. Conclusions: Herein, we identify MPO as a mediator of monocyte and macrophage recruitment and activation after MI. Impacting plasma MPO levels may therefore offer a therapeutic target to modulate inflammatory responses and subsequent tissue remodelling post MI.

https://dgk.org/kongress_programme/jt2022/aV25.html