Preeclampsia Is Associated with Alterations in DNA Methylation of Genes Involved in Collagen Metabolism
Preeclampsia Is Associated with Alterations in DNA Methylation of Genes Involved in Collagen Metabolism
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DOI：
10.1016/j.ajpath.2012.06.019
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发表时间：
2012-10-01
影响因子：
6
通讯作者：
Walsh, Scott W.
中科院分区：
文献类型：
--
作者：
Mousa, Ahmad A.;Cappello, Renato E.;Walsh, Scott W.
母体血管功能障碍是先兆子痫的标志。最近描述的先兆子痫的血管表型涉及内皮细胞、血管平滑肌和浸润性中性粒细胞中基质金属蛋白酶-1（MMP-1）的表达增加。相比之下，金属蛋白酶组织抑制剂-1（TIMP-1）和胶原蛋白Ia 1型的表达在血管中减少或不改变，表明先兆子痫中血管胶原蛋白降解和合成的不平衡。在本研究中，我们探讨了DNA甲基化对参与胶原代谢的基因表达改变的可能贡献。我们分析了正常孕妇和先兆子痫妇女网膜动脉中DNA甲基化的差异，并确定DNA甲基化降低是否会增加培养的血管平滑肌细胞和HL-60细胞系中MMP-1的表达。几个MMP基因，包括MMP 1和MMP 8，显着减少甲基化在先兆子痫网膜动脉，而TIMP和COL基因要么显着更多的甲基化或没有显着变化，在其DNA甲基化状态与正常妊娠相比。实验诱导的DNA低甲基化增加培养的血管平滑肌细胞和MMP-1细胞中MMP-1的表达。我们的研究结果表明，表观遗传调控有助于参与胶原代谢的基因在先兆子痫妇女的血管中的不平衡。(Am J Pathol 2012，181：1455-1463; http：//dx·doi·org/10·1016/j·ajpath·2012·06·019）
Maternal vascular dysfunction is a hallmark of preeclampsia. A recently described vascular phenotype of preeclampsia involves increased expression of matrix metalloproteinase-1 (MMP-1) in endothelial cells, vascular smooth muscle, and infiltrating neutrophils. In contrast, the expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) and collagen type la 1 is either reduced or not changed in the vessels, suggesting an imbalance in vessel collagen degradation and synthesis in preeclampsia. In the present study, we explored the possible contribution of DNA methylation to the altered expression of genes involved in collagen metabolism. We assayed the differences in DNA methylation in omental arteries from normal pregnant and preeclamptic women, and determined whether reduced DNA methylation increases the expression of MMP-1 in cultured vascular smooth muscle cells and a neutrophil-like cell line, HL-60. Several MMP genes, including MMP1 and MMP8, were significantly less methylated in preeclamptic omental arteries, whereas TIMP and COL genes either were significantly more methylated or had no significant change in their DNA methylation status compared with normal pregnancy. Experimentally induced DNA hypomethylation increased MMP-1 expression in cultured vascular smooth muscle cells and MMP-1 cells. Our findings suggest that epigenetic regulation contributes to the imbalance in genes involved in collagen metabolism in blood vessels of preeclamptic women. (Am J Pathol 2012, 181:1455-1463; http://dx.doi.org/10.1016/j.ajpath.2012.06.019)