Epigenetic regulation of NKG2D ligands is involved in exacerbated atherosclerosis development in Sirt6 heterozygous mice.
Epigenetic regulation of NKG2D ligands is involved in exacerbated atherosclerosis development in Sirt6 heterozygous mice.
复制标题
NKG2D配体的表观遗传调控参与Sirt6杂合小鼠动脉粥样硬化的加剧
DOI：
10.1038/srep23912
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发表时间：
2016-04-05
影响因子：
4.6
通讯作者：
Liu DP
中科院分区：
文献类型：
--
作者：
Zhang ZQ;Ren SC;Tan Y;Li ZZ;Tang X;Wang TT;Hao DL;Zhao X;Chen HZ;Liu DP
Sirt6是III类组蛋白去乙酰化酶家族的成员，与衰老和长寿有关。Sirt6缺陷小鼠表现出衰老样表型，而Sirt6转基因雄性小鼠表现出寿命延长。Sirt6作为一种肿瘤抑制因子，Sirt6的缺乏会导致心脏肥厚和心力衰竭。Sirt6是否参与动脉粥样硬化（心血管疾病的主要原因）的发展尚不清楚。我们发现Sirt6在人类动脉粥样硬化斑块中的表达低于对照组。Sirt6+/−ApoE−/−和ApoE−/−小鼠饲喂高脂饲料16周后，Sirt6+/−ApoE−/−小鼠斑块形成增加，斑块不稳定。此外，Sirt6下调会增加NKG2D配体的表达，从而导致细胞因子表达增加。阻断NKG2D配体几乎完全阻断了这种作用。机制上，Sirt6结合NKG2D配体基因启动子，调节H3K9和H3K56乙酰化水平。
Sirt6 is a member of the class III histone deacetylase family which is associated with aging and longevity. Sirt6 deficient mice show an aging-like phenotype, while male transgenic mice of Sirt6 show increased longevity. Sirt6 acts as a tumor suppressor and deficiency of Sirt6 leads to cardiac hypertrophy and heart failure. Whether Sirt6 is involved in atherosclerosis development, the major cause of cardiovascular diseases, is unknown. We found that the expression of Sirt6 is lower in human atherosclerotic plaques than that in controls. When Sirt6+/−ApoE−/−and ApoE−/−mice are fed with high fat diet for 16 weeks, Sirt6+/−ApoE−/−mice show increased plaque fromation and exhibit feature of plaque instability. Furthermore, Sirt6 downregulation increases expression of NKG2D ligands, which leads to increased cytokine expression. Blocking NKG2D ligand almost completely blocks this effect. Mechanistically, Sirt6 binds to promoters of NKG2D ligand genes and regulates the H3K9 and H3K56 acetylation levels.