NEIL3-Dependent Regulation of Cardiac Fibroblast Proliferation Prevents Myocardial Rupture | Zendy

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

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NEIL3-Dependent Regulation of Cardiac Fibroblast Proliferation Prevents Myocardial Rupture

Author(s) -

Maria Belland Olsen,

Gunn A. Hildrestrand,

Katja Scheffler,

Leif Erik Vinge,

Katrine Alfsnes,

Vuk Palibrk,

Junbai Wang,

Christine Gran Neurauter,

Luisa Luna,

Jostein Johansen,

Jonas Øgaard,

Ingrid Kristine 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 Vanessa Finsen

Publication year - 2017

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2016.12.009

Subject(s) - fibroblast , extracellular matrix , myofibroblast , microbiology and biotechnology , cardiac rupture , downregulation and upregulation , cancer research , dna methylation , cell growth , biology , myocardial infarction , gene expression , pathology , gene , medicine , cell culture , genetics , fibrosis

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.

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