NEIL3 依赖性调控心脏成纤维细胞增殖可预防心肌破裂。
NEIL3-Dependent Regulation of Cardiac Fibroblast Proliferation Prevents Myocardial Rupture.
机构信息
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.
Department of Microbiology, Oslo University Hospital and University of Oslo, 0424 Oslo, Norway.
出版信息
Cell Rep. 2017 Jan 3;18(1):82-92. doi: 10.1016/j.celrep.2016.12.009.
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.
心肌梗死（MI）引发修复反应，涉及成纤维细胞增殖和分化，驱动细胞外基质的调节，这对于形成稳定的瘢痕是必要的。最近，有研究表明碱基切除修复酶 NEIL3 的一个基因变异与人类 MI 风险增加有关。在这里，我们报告了心力衰竭患者心肌中 NEIL3 表达升高，以及在 MI 后小鼠心肌中 NEIL3 的明显上调，特别是在富含成纤维细胞的细胞部分。Neil3 小鼠在 MI 导致的心肌破裂后死亡率增加。对 5-甲基胞嘧啶（5mC）和 5-羟甲基胞嘧啶（5hmC）的全基因组分析揭示了心脏表观基因组的变化，包括与 MI 后转录反应相关的基因。差异甲基化基因富集在与增殖和肌成纤维细胞分化相关的途径中。因此，Neil3 破裂的心脏显示出成纤维细胞和肌成纤维细胞的增殖增加。我们提出，NEIL3 依赖性 DNA 甲基化调节调节心脏成纤维细胞的增殖，从而影响 MI 后的细胞外基质调节。
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