Glucose-independent persistence of PAI-1 gene expression and H3K4 tri-methylation in type 1 diabetic mouse endothelium: implication in metabolic memory.
Glucose-independent persistence of PAI-1 gene expression and H3K4 tri-methylation in type 1 diabetic mouse endothelium: implication in metabolic memory.
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DOI：
10.1016/j.bbrc.2013.02.064
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发表时间：
2013-03
影响因子：
3.1
通讯作者：
Fumihiko Takizawa;S. Mizutani;Yoshihiro Ogawa;N. Sawada
中科院分区：
文献类型：
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作者：
Fumihiko Takizawa;S. Mizutani;Yoshihiro Ogawa;N. Sawada
1型和2型糖尿病的临床试验已经确定了一种被称为“代谢记忆”的现象，其中先前的高血糖期导致对心血管事件的长期有害影响。新出现的证据表明，短暂的高血糖暴露的人内皮细胞诱导组蛋白3赖氨酸4单甲基化（H3 K4 me 1）的启动子和RelA和IL-8基因的持续mRNA表达，表明表观遗传组蛋白修饰和染色质结构重塑是代谢记忆的关键事件。然而，这一新兴的假设，关键是要测试在体内糖尿病的疾病过程中的相关性，并为更广泛的适用性，涉及内皮功能障碍的基因阵列。为了解决这一问题，我们使用链脲佐菌素诱导的高血糖8周的1型糖尿病小鼠模型，并分离内皮细胞，这些细胞在分离后新鲜使用或在正常血糖条件下培养2至3周后使用。糖尿病小鼠内皮细胞中的mRNA表达谱显示Serpine 1编码派-1的显著和持续上调，PAI-1是导致糖尿病血栓性疾病的低纤溶介质，沿着Rock 2，Fn 1和Ccl 2，而只有Serpine 1在高糖处理的小鼠内皮细胞中持续升高。1型糖尿病小鼠内皮细胞的染色体免疫沉淀分析显示Serpine 1启动子上H3 K4三甲基化的主要富集，这表明糖尿病小鼠与高糖处理的人内皮细胞相比具有独特的表观遗传调节。我们的研究证明了将体内糖尿病模型与高糖处理的细胞培养相结合以更好地评估与疾病相关的表观遗传机制的重要性。
Clinical trials with type 1 and type 2 diabetes have identified a phenomenon known as “metabolic memory” in which previous periods of hyperglycemia result in the long-lasting deleterious impact on cardiovascular events. Emerging evidence shows that transient hyperglycemic exposure of human endothelial cells induces histone 3 lysine 4 mono-methylation (H3K4me1) on the promoter and persistent mRNA expression of RelA and IL-8 genes, suggesting that epigenetic histone modification and chromatin structure remodeling is a key event underlying metabolic memory. This burgeoning hypothesis, however, critically remains to be tested for relevance in the disease process of diabetes in vivo, and for broader applicability to an array of genes involved in endothelial dysfunction. To address this, we used type 1 diabetes mouse model induced by streptozocin to be hyperglycemic for 8weeks, and isolated endothelial cells that were used either freshly after isolation or after 2 to 3-week cell culture in normoglycemic conditions. mRNA expression profiling in diabetic mouse endothelial cells revealed significant and persistent up-regulation of Serpine1 encoding PAI-1, the hypo-fibrinolytic mediator leading to thrombotic diseases in diabetes, along with Rock2, Fn1 and Ccl2, whereas only Serpine 1 was persistently elevated in high glucose-treated mouse endothelial cells. Chromosome immunoprecipitation assay in type 1 diabetic mouse endothelial cells showed predominant enrichment of H3K4 tri-methylation on Serpine1 promoter, suggesting a unique epigenetic regulation in diabetic mice as opposed to high glucose-treated human ECs. Our study demonstrates the importance of combining in vivo models of diabetes with high glucose-treated cell culture to better assess the epigenetic mechanisms relevant to disease.