NEIL3-Dependent Regulation of Cardiac Fibroblast Proliferation Prevents Myocardial Rupture

Maria B Olsen; Gunn A Hildrestrand; Katja Scheffler; Leif Erik Vinge; Katrine Alfsnes; Vuk Palibrk; Junbai Wang; Christine G Neurauter; Luisa Luna; Jostein Johansen; Jonas D S Øgaard; Ingrid K Ohm; Geir Slupphaug; Anna Kuśnierczyk; Arnt E Fiane; Sverre-Henning Brorson; Lili Zhang; Lars Gullestad; William E Louch; Per Ole Iversen; Ingunn Østlie; Arne Klungland; Geir Christensen; Ivar Sjaastad; Pål Sætrom; Arne Yndestad; Pål Aukrust; Magnar Bjørås; Alexandra V Finsen

doi:10.1016/j.celrep.2016.12.009

NEIL3-Dependent Regulation of Cardiac Fibroblast Proliferation Prevents Myocardial Rupture

Cell Rep. 2017 Jan 3;18(1):82-92. doi: 10.1016/j.celrep.2016.12.009.

Authors

Maria B Olsen¹, Gunn A Hildrestrand², Katja Scheffler³, Leif Erik Vinge⁴, Katrine Alfsnes¹, Vuk Palibrk³, Junbai Wang⁵, Christine G Neurauter², Luisa Luna², Jostein Johansen⁶, Jonas D S Øgaard⁷, Ingrid K Ohm⁸, Geir Slupphaug⁹, Anna Kuśnierczyk⁹, Arnt E Fiane¹⁰, Sverre-Henning Brorson⁵, Lili Zhang¹¹, Lars Gullestad⁴, William E Louch¹², Per Ole Iversen¹³, Ingunn Østlie⁵, Arne Klungland², Geir Christensen¹⁴, Ivar Sjaastad¹⁴, Pål Sætrom¹⁵, Arne Yndestad¹, Pål Aukrust¹⁶, Magnar Bjørås¹⁷, Alexandra V Finsen⁴

Affiliations

¹ 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.
² Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
³ Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
⁴ 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.
⁵ Department of Pathology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
⁶ Bioinformatics Core Facility-BioCore , Norwegian University of Science and Technology, 7491 Trondheim, Norway.
⁷ Research Institute of Internal Medicine, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
⁸ 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.
⁹ 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.
¹⁰ Department of Cardiothoracic Surgery, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
¹¹ Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
¹² 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.
¹³ Department of Haematology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway; Department of Nutrition, University of Oslo, 0317 Oslo, Norway.
¹⁴ 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.
¹⁵ 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.
¹⁶ 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.
¹⁷ 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.

PMID: 28052262
DOI: 10.1016/j.celrep.2016.12.009

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.

Keywords: DNA glycosylase; DNA methylation; NEIL3; base excision repair; cardiac fibroblast; cardiac myofibroblast; cardiac rupture; epigenome; extracellular matrix modulation; myocardial infarction.

MeSH terms

5-Methylcytosine / analogs & derivatives
5-Methylcytosine / metabolism
Cell Proliferation
Collagen / metabolism
Connective Tissue Diseases / genetics
Connective Tissue Diseases / pathology
DNA Damage
DNA Methylation / genetics
Endodeoxyribonucleases / deficiency
Endodeoxyribonucleases / metabolism*
Fibroblasts / metabolism*
Fibroblasts / pathology*
Gene Expression Profiling
Gene Expression Regulation
Heart Failure / genetics
Heart Failure / pathology
Heart-Assist Devices
Humans
Leukocytes / pathology
Matrix Metalloproteinase 2 / metabolism
Myocardial Infarction / pathology
Myocardium / metabolism*
Myocardium / pathology*
Myofibroblasts / metabolism
Myofibroblasts / pathology
N-Glycosyl Hydrolases / metabolism*
Oxidation-Reduction
Phenotype
Sequence Analysis, RNA
Survival Analysis
Time Factors

Substances

5-hydroxymethylcytosine
5-Methylcytosine
Collagen
Endodeoxyribonucleases
NEIL3 protein, mouse
N-Glycosyl Hydrolases
NEIL3 protein, human
Matrix Metalloproteinase 2