NEIL3-Dependent Regulation of Cardiac Fibroblast Proliferation Prevents Myocardial Rupture

Publication date: 3 January 2017
Source:Cell Reports, Volume 18, Issue 1
Author(s): 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
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.

Graphical abstract

Teaser

Olsen et al. show that the DNA repair enzyme, NEIL3, has impact on survival after myocardial infarction in mice. They find that NEIL3 regulates cardiac fibroblast proliferation and thereby affects extracellular matrix modulation. They propose that NEIL3 operates by regulating DNA methylation of genes important for fibroblast proliferation and differentiation.


from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2iArMUV
via IFTTT