Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype
Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype
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DOI：
10.1093/hmg/ddt614
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发表时间：
2014-04-15
影响因子：
3.5
通讯作者：
Baugh, John A.
中科院分区：
文献类型：
--
作者：
Watson, Chris J.;Collier, Patrick;Baugh, John A.
冠状动脉疾病和心肌梗死引起的缺血导致异常心室重构和心脏纤维化。这部分通过在常驻成纤维细胞中积累基因表达变化而发生，导致过度活跃的纤维化表型。长期适应缺氧损伤可能需要显着修改染色质结构，以保持纤维化表型。表观遗传变化可能在调节心脏内缺氧诱导的纤维化中起重要作用。因此，本研究的目的是探讨缺氧对心脏成纤维细胞的潜在促纤维化影响，并确定DNA甲基化的改变是否在此过程中发挥作用。本研究发现，在人类心脏组织中，缺氧程度与胶原1和α-平滑肌肌动蛋白（ASMA）表达增加有关。此外，人心脏成纤维细胞暴露于长时间缺氧导致促纤维化状态。这些缺氧诱导的促纤维化变化与整体DNA超甲基化和DNA甲基转移酶（DNMT）DNMT 1和DNMT 3B表达增加相关。这些甲基化酶的表达被证明是由缺氧诱导因子（HIF）-1调节。使用siRNA阻断DNMT 3B表达显著降低胶原1和ASMA表达。此外，DNMT抑制剂5-氮杂-2-脱氧胞苷的应用抑制了TGF的促纤维化作用。表观遗传修饰和表观遗传机制的变化，确定在长期缺氧的心脏成纤维细胞可能有助于缺血环境的促纤维化的性质。靶向上调缺血性心脏病中DNMT的表达可能被证明是一种有价值的治疗方法。
Ischemia caused by coronary artery disease and myocardial infarction leads to aberrant ventricular remodeling and cardiac fibrosis. This occurs partly through accumulation of gene expression changes in resident fibroblasts, resulting in an overactive fibrotic phenotype. Long-termadaptation to a hypoxic insult is likely to require significant modification of chromatin structure in order to maintain the fibrotic phenotype. Epigenetic changes may play an important role in modulating hypoxia-induced fibrosis within the heart. Therefore, the aim of the study was to investigate the potential pro-fibrotic impact of hypoxia on cardiac fibroblasts and determine whether alterations in DNA methylation could play a role in this process.This study found that within human cardiac tissue, the degree of hypoxia was associated with increased expression of collagen 1 and alpha-smooth muscle actin (ASMA). In addition, human cardiac fibroblast cells exposed to prolonged 1 hypoxia resulted in a pro-fibrotic state. These hypoxia-induced pro-fibrotic changes were associated with global DNA hypermethylation and increased expression of the DNA methyltransferase (DNMT) enzymes DNMT1 and DNMT3B. Expression of these methylating enzymes was shown to be regulated by hypoxia-inducible factor (HIF)-1. Using siRNA to block DNMT3B expression significantly reduced collagen 1 and ASMA expression. In addition, application of the DNMT inhibitor 5-aza-2-deoxycytidine suppressed the pro-fibrotic effects of TGF. Epigenetic modifications and changes in the epigenetic machinery identified in cardiac fibroblasts during prolonged hypoxia may contribute to the pro-fibrotic nature of the ischemic milieu. Targeting up-regulated expression of DNMTs in ischemic heart disease may prove to be a valuable therapeutic approach.