Remodeling of the endothelial cell transcriptional program via paracrine and DNA-binding activities of MPO
Ruiyuan Zheng,
Kyle Moynahan,
Theodoros Georgomanolis,
Egor Pavlenko,
Simon Geissen,
Athanasia Mizi,
Simon Grimm,
Harshal Nemade,
Rizwan Rehimi,
Jil Bastigkeit,
Jan-Wilm Lackmann,
Matti Adam,
Alvaro Rada-Iglesias,
Peter Nuernberg,
Anna Klinke,
Simon Poepsel,
Stephan Baldus,
Argyris Papantonis,
Yulia Kargapolova
Affiliations
Ruiyuan Zheng
Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
Kyle Moynahan
Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
Theodoros Georgomanolis
Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
Egor Pavlenko
Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
Simon Geissen
Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
Athanasia Mizi
Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany
Simon Grimm
Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
Harshal Nemade
Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
Rizwan Rehimi
Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
Jil Bastigkeit
Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
Jan-Wilm Lackmann
Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cluster of Excellence on Cellular Stress Responses in Age-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
Matti Adam
Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
Alvaro Rada-Iglesias
Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), University of Cantabria, 39011 Santander, Spain
Peter Nuernberg
Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany
Anna Klinke
Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
Simon Poepsel
Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
Stephan Baldus
Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany
Argyris Papantonis
Institute of Pathology, University Medical Center Göttingen, 37075 Göttingen, Germany; Corresponding author
Yulia Kargapolova
Department III of Internal Medicine, Heart Center, Faculty of Medicine and University Hospital of Cologne, 50937 Cologne, Germany; Corresponding author
Summary: Myeloperoxidase (MPO) is an enzyme that functions in host defense. MPO is released into the vascular lumen by neutrophils during inflammation and may adhere and subsequently penetrate endothelial cells (ECs) coating vascular walls. We show that MPO enters the nucleus of ECs and binds chromatin independently of its enzymatic activity. MPO drives chromatin decondensation at its binding sites and enhances condensation at neighboring regions. It binds loci relevant for endothelial-to-mesenchymal transition (EndMT) and affects the migratory potential of ECs. Finally, MPO interacts with the RNA-binding factor ILF3 thereby affecting its relative abundance between cytoplasm and nucleus. This interaction leads to change in stability of ILF3-bound transcripts. MPO-knockout mice exhibit reduced number of ECs at scar sites following myocardial infarction, indicating reduced neovascularization. In summary, we describe a non-enzymatic role for MPO in coordinating EndMT and controlling the fate of endothelial cells through direct chromatin binding and association with co-factors.
