Promoter region methylation and reduced expression of thrombospondin-1 after oxygen-glucose deprivation in murine cerebral endothelial cells
Promoter region methylation and reduced expression of thrombospondin-1 after oxygen-glucose deprivation in murine cerebral endothelial cells
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DOI：
10.1038/sj.jcbfm.9600304
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发表时间：
2006-12-01
影响因子：
6.3
通讯作者：
Hsu, Chung Y.
中科院分区：
文献类型：
--
作者：
Hu, Chaur-Jong;Chen, Shang-Der;Hsu, Chung Y.
血管新生是对缺血的反应。血栓反应蛋白-1 （TSP-1）是一种有效的血管抑制因子。沉默TSP-1表达可能有助于缺血后血管生成。相反，TSP-1的上调可能终止缺血后血管生成。抑制TSP-1表达的可能机制是其启动子区域的DNA甲基化。脑缺血后DNA甲基化已被报道。本研究旨在探讨体外小鼠脑内皮细胞（CECs）缺氧-葡萄糖剥夺（OGD）后TSP-1启动子区甲基化是否调节其表达。亚致死OGD增加了cec中TSP-1启动子区域的甲基化程度，同时降低了TSP-1 mRNA和蛋白的表达。再氧化后，TSP-1启动子区域的去甲基化导致TSP-1 mRNA和蛋白表达的恢复。OGD后，TSP-1启动子区的甲基化程度与TSP-1基因mRNA和蛋白水平的表达程度呈负相关。氧-葡萄糖剥夺诱导的TSP-1 mRNA水平降低不伴有mRNA稳定性的改变。这些发现提出了一种可能性，即OGD下调TSP-1表达至少部分是由于其启动子区域的甲基化。
Angiogenesis is induced in response to ischemia. Thrombospondin-1 (TSP-1) is a potent angiostatic factor. Silencing of TSP-1 expression may contribute to the postischemic angiogenesis. Upregulation of TSP-1, in contrast, may terminate the postischemic angiogenesis. A possible mechanism that silences TSP-1 expression is the DNA methylation of its promoter region. DNA methylation has been reported following cerebral ischemia. The present study aimed to explore whether methylation of the promoter region of TSP-1 regulates its expression after oxygen-glucose deprivation (OGD) in murine cerebral endothelial cells (CECs) in vitro. Sublethal OGD increased the extent of methylation of the promoter region of TSP-1 with a concurrent decrease in TSP-1 mRNA and protein expression in CECs. After reoxygenation, demethylation of the TSP-1 promoter region led to the restoration of TSP-1 mRNA and protein expression. The extent of methylation of the promoter region of TSP-1 was inversely correlated with the extent of TSP-1 gene expression at mRNA and protein levels after OGD. Oxygen-glucose deprivation-induced reduction in the TSP-1 mRNA level was not accompanied by a change in mRNA stability. These findings raise the possibility that OGD downregulation of TSP-1 expression is at least in part due to methylation of its promoter region.