Cell reports · 2017
NEIL3-Dependent Regulation of Cardiac Fibroblast Proliferation Prevents Myocardial Rupture.
СтатьяНазвание и аннотация: Перевод в очереди
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Olsen Maria B, Hildrestrand Gunn A, Scheffler Katja, Vinge Leif Erik, Alfsnes Katrine, Palibrk Vuk, Wang Junbai, Neurauter Christine G, Luna Luisa, Johansen Jostein, Øgaard Jonas D S, Ohm Ingrid K, Slupphaug Geir, Kuśnierczyk Anna, Fiane Arnt E, Brorson Sverre-Henning, Zhang Lili, Gullestad Lars, Louch William E, Iversen Per Ole, Østlie Ingunn, Klungland Arne, Christensen Geir, Sjaastad Ivar, Sætrom Pål, Yndestad Arne, Aukrust Pål, Bjørås Magnar, Finsen Alexandra V
Аннотация
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.
Предметные рубрики MeSH
5-MethylcytosineCell ProliferationCollagenConnective Tissue DiseasesDNA DamageDNA MethylationEndodeoxyribonucleasesFibroblastsGene Expression ProfilingGene Expression RegulationHeart FailureHeart-Assist DevicesHumansLeukocytesMatrix Metalloproteinase 2Myocardial InfarctionMyocardiumMyofibroblastsN-Glycosyl HydrolasesOxidation-ReductionPhenotypeSequence Analysis, RNASurvival AnalysisTime Factors