title: NEIL3-Dependent Regulation of Cardiac Fibroblast Proliferation Prevents Myocardial Rupture.
abstract: Myocardial infarction (MI) triggers a reparative response involving fibroblast proliferation and differentiation driving extracellular matrix modulation necessary to form a stabilizing scar. Recently, it was shown that a genetic variant of the base excision repair enzyme NEIL3 was associated with increased risk of MI in humans. Here, we report elevated myocardial NEIL3 expression in heart failure patients and marked myocardial upregulation of Neil3 after MI in mice, especially in a fibroblast-enriched cell fraction. Neil3-/-mice show increased mortality after MI caused by myocardial rupture. Genome-wide analysis of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) reveals changes in the cardiac epigenome, including in genes related to the post-MI transcriptional response. Differentially methylated genes are enriched in pathways related to proliferation and myofibroblast differentiation. Accordingly, Neil3-/-ruptured hearts show increased proliferation of fibroblasts and myofibroblasts. We propose that NEIL3-dependent modulation of DNA methylation regulates cardiac fibroblast proliferation and thereby affects extracellular matrix modulation after MI.
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Center for Heart Failure Research, University of Oslo, 0317 Oslo, Norway; K.G. Jebsen Inflammation Research Centre, University of Oslo, 0317 Oslo, Norway.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Olsen
authors.affiliation: Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
authors.forename: Gunn A
authors.initials: GA
authors.lastname: Hildrestrand
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
authors.forename: Katja
authors.initials: K
authors.lastname: Scheffler
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Department of Cardiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Center for Heart Failure Research, University of Oslo, 0317 Oslo, Norway.
authors.forename: Leif Erik
authors.initials: LE
authors.lastname: Vinge
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Center for Heart Failure Research, University of Oslo, 0317 Oslo, Norway; K.G. Jebsen Inflammation Research Centre, University of Oslo, 0317 Oslo, Norway.
authors.forename: Katrine
authors.initials: K
authors.lastname: Alfsnes
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
authors.forename: Vuk
authors.initials: V
authors.lastname: Palibrk
authors.affiliation: Department of Pathology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
authors.forename: Junbai
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
authors.forename: Christine G
authors.initials: CG
authors.lastname: Neurauter
authors.affiliation: Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
authors.forename: Luisa
authors.initials: L
authors.lastname: Luna
authors.affiliation: Bioinformatics Core Facility-BioCore , Norwegian University of Science and Technology, 7491 Trondheim, Norway.
authors.forename: Jostein
authors.initials: J
authors.lastname: Johansen
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
authors.forename: Jonas D S
authors.initials: JDS
authors.lastname: Øgaard
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Center for Heart Failure Research, University of Oslo, 0317 Oslo, Norway.
authors.forename: Ingrid K
authors.initials: IK
authors.lastname: Ohm
authors.affiliation: Proteomics and Metabolomics Core Facility-PROMEC, Norwegian University of Science and Technology, 7491 Trondheim, Norway; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Slupphaug
authors.affiliation: Proteomics and Metabolomics Core Facility-PROMEC, Norwegian University of Science and Technology, 7491 Trondheim, Norway; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
authors.forename: Anna
authors.initials: A
authors.lastname: Kuśnierczyk
authors.affiliation: Department of Cardiothoracic Surgery, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
authors.forename: Arnt E
authors.initials: AE
authors.lastname: Fiane
authors.affiliation: Department of Pathology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
authors.forename: Sverre-Henning
authors.initials: SH
authors.lastname: Brorson
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Department of Cardiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Center for Heart Failure Research, University of Oslo, 0317 Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Gullestad
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Center for Heart Failure Research, University of Oslo, 0317 Oslo, Norway.
authors.forename: William E
authors.initials: WE
authors.lastname: Louch
authors.affiliation: Department of Haematology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Department of Nutrition, University of Oslo, 0317 Oslo, Norway.
authors.forename: Per Ole
authors.initials: PO
authors.lastname: Iversen
authors.affiliation: Department of Pathology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
authors.forename: Ingunn
authors.initials: I
authors.lastname: Østlie
authors.affiliation: Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
authors.forename: Arne
authors.initials: A
authors.lastname: Klungland
authors.affiliation: Department of Cardiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Center for Heart Failure Research, University of Oslo, 0317 Oslo, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.affiliation: Department of Cardiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Center for Heart Failure Research, University of Oslo, 0317 Oslo, Norway.
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.affiliation: Bioinformatics Core Facility-BioCore , Norwegian University of Science and Technology, 7491 Trondheim, Norway; Department of Computer and Information Science, Norwegian University of Science and Technology, 7491 Trondheim, Norway; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Sætrom
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Center for Heart Failure Research, University of Oslo, 0317 Oslo, Norway; K.G. Jebsen Inflammation Research Centre, University of Oslo, 0317 Oslo, Norway.
authors.forename: Arne
authors.initials: A
authors.lastname: Yndestad
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; K.G. Jebsen Inflammation Research Centre, University of Oslo, 0317 Oslo, Norway.
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.affiliation: Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway. Electronic address: magnar.bjoras@ntnu.no.
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
authors.affiliation: Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Department of Cardiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Center for Heart Failure Research, University of Oslo, 0317 Oslo, Norway.
authors.forename: Alexandra V
authors.initials: AV
authors.lastname: Finsen
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D003240:Connective Tissue Diseases / Q000235:genetics / Q000473:pathology; D004249:DNA Damage; D019175:DNA Methylation / Q000235:genetics; D004706:Endodeoxyribonucleases / Q000172:deficiency / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000473:pathology; D006353:Heart-Assist Devices; D006801:Humans; D007962:Leukocytes / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D009699:N-Glycosyl Hydrolases / Q000378:metabolism*; D010084:Oxidation-Reduction; D010641:Phenotype; D017423:Sequence Analysis, RNA; D016019:Survival Analysis; D013997:Time Factors
chemical_list: C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003094:Collagen; D004706:Endodeoxyribonucleases; C540052:NEIL3 protein, mouse; D009699:N-Glycosyl Hydrolases; C468764:NEIL3 protein, human; D020778:Matrix Metalloproteinase 2
keywords: DNA glycosylase; DNA methylation; NEIL3; base excision repair; cardiac fibroblast; cardiac myofibroblast; cardiac rupture; epigenome; extracellular matrix modulation; myocardial infarction