title: Epigenetic regulation of NKG2D ligands is involved in exacerbated atherosclerosis development in Sirt6 heterozygous mice.
abstract: 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.
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 5 Dong Dan San Tiao, Beijing 100005, P.R. China.
authors.forename: Zhu-Qin
authors.initials: ZQ
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 5 Dong Dan San Tiao, Beijing 100005, P.R. China.
authors.forename: Si-Chong
authors.initials: SC
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 5 Dong Dan San Tiao, Beijing 100005, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 5 Dong Dan San Tiao, Beijing 100005, P.R. China.
authors.forename: Zuo-Zhi
authors.initials: ZZ
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 5 Dong Dan San Tiao, Beijing 100005, P.R. China.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 5 Dong Dan San Tiao, Beijing 100005, P.R. China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 5 Dong Dan San Tiao, Beijing 100005, P.R. China.
authors.forename: De-Long
authors.initials: DL
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 5 Dong Dan San Tiao, Beijing 100005, P.R. China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 5 Dong Dan San Tiao, Beijing 100005, P.R. China.
authors.forename: Hou-Zao
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 5 Dong Dan San Tiao, Beijing 100005, P.R. China.
authors.forename: De-Pei
authors.initials: DP
authors.lastname: Liu
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D016894:Endarterectomy, Carotid; D044127:Epigenesis, Genetic; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics*; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D037761:Sirtuins / Q000235:genetics*
chemical_list: D001057:Apolipoproteins E; C527086:Klrk1 protein, mouse; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; C501860:Sirt6 protein, mouse; D037761:Sirtuins