1. NEIL3-Dependent Regulation of Cardiac Fibroblast Proliferation Prevents Myocardial Rupture
- Author
-
Christine G. Neurauter, Vuk Palibrk, Lili Zhang, Pål Sætrom, William E. Louch, Ingunn Østlie, Sverre-Henning Brorson, Lars Gullestad, Junbai Wang, Ivar Sjaastad, Ingrid Kristine Ohm, Katrine Alfsnes, Magnar Bjørås, Jonas Øgaard, Geir Christensen, Arne Yndestad, Per Ole Iversen, Arnt E. Fiane, Maria Belland Olsen, Geir Slupphaug, Gunn A. Hildrestrand, Pål Aukrust, Jostein Johansen, Arne Klungland, Anna Kuśnierczyk, Leif Erik Vinge, Luisa Luna, Alexandra Vanessa Finsen, and Katja Scheffler
- Subjects
0301 basic medicine ,Time Factors ,Myocardial Infarction ,Biology ,Myocardial rupture ,General Biochemistry, Genetics and Molecular Biology ,Extracellular matrix ,03 medical and health sciences ,Downregulation and upregulation ,Leukocytes ,medicine ,Humans ,Myocardial infarction ,Connective Tissue Diseases ,Myofibroblasts ,Fibroblast ,N-Glycosyl Hydrolases ,Cell Proliferation ,Heart Failure ,Regulation of gene expression ,Endodeoxyribonucleases ,Sequence Analysis, RNA ,Gene Expression Profiling ,Myocardium ,Cardiac Rupture ,DNA Methylation ,Fibroblasts ,medicine.disease ,Survival Analysis ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,5-Methylcytosine ,Cancer research ,Matrix Metalloproteinase 2 ,Collagen ,Heart-Assist Devices ,Oxidation-Reduction ,Myofibroblast ,DNA Damage - 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. © 2017 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
- Published
- 2017