Trichostatin A exacerbates atherosclerosis in low density lipoprotein receptor-deficient mice
Trichostatin A exacerbates atherosclerosis in low density lipoprotein receptor-deficient mice
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DOI：
10.1161/01.atv.0000184758.07257.88
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发表时间：
2005-11-01
影响因子：
8.7
通讯作者：
Oh, GT
中科院分区：
文献类型：
--
作者：
Choi, JH;Nam, KH;Oh, GT
目的：组蛋白乙酰化已被证明参与了一组有限的细胞基因的表达，包括各种促炎分子。我们的目的是研究组蛋白乙酰化与动脉粥样硬化的关系。方法与结果：低密度脂蛋白（LDL）受体缺陷（-/-）小鼠喂食致动脉粥样硬化饮食4周或8周后，曲古抑素A (TSA)，一种特异性组蛋白去乙酰化酶抑制剂，在不改变血脂谱的情况下加剧动脉粥样硬化。当我们检测TSA对RAW264.7巨噬细胞氧化LDL （oxLDL）受体表达的影响时，我们发现TSA增加了CD36 mRNA和蛋白，以及CD36的细胞表面表达。TSA也增加了CD36启动子区域的乙酰化。TSA可增强RAW264.7巨噬细胞对1,1'-二十八烷基-3,3,3',3'-四甲基吲哚碳青过胆酸（Dil）标记的oxLDL的摄取。此外，TSA处理增加了主动脉CD36 mRNA的表达，SRA、肿瘤坏死因子(TNF)- α和血管细胞粘附分子-1 （VCAM-1）也升高，而IL-6和IL-1 β的表达降低。结论：组蛋白乙酰化可能通过调节oxLDL受体和一些促动脉粥样硬化基因的表达在动脉粥样硬化中起一定作用。因此，我们的研究结果表明，组蛋白乙酰化升高可能影响动脉粥样硬化的进展。
Objective-Histone acetylation has been shown to be involved in expression of a restricted set of cellular genes including various proinflammatory molecules. We aimed to investigate the relationship between histone acetylation and atherosclerosis.Methods and Results-In low-density lipoprotein (LDL) receptor-deficient (Ldlr(-/-)) mice fed an atherogenic diet for 4 or 8 weeks, trichostatin A (TSA), a specific histone deacetylase inhibitor, exacerbated atherosclerosis without alteration on plasma lipid profiles. When we assayed the effects of TSA on expressions of oxidized LDL (oxLDL) receptors on RAW264.7 macrophage, we found that TSA increased CD36 mRNA and protein, as well as cell surface expression of CD36. TSA also increased acetylation at the CD36 promoter region. The uptake of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine percholate (Dil)-labeled oxLDL was enhanced in RAW264.7 macrophage by TSA. Furthermore, TSA treatment increased CD36 mRNA expression in aorta, and SRA, tumor necrosis factor (TNF)-alpha, and vascular cell adhesion molecule-1 (VCAM-1) were also elevated, whereas IL-6 and IL-1 beta expressions were decreased.Conclusions-Our findings suggest that histone acetylation could play some role in atherogenesis by modulating expressions of oxLDL receptor and some proatherogenic genes. Therefore, our results indicate that increased histone acetylation may affect the progress of atherosclerosis.