Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.
Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.
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DOI：
10.1126/science.aag1381
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发表时间：
2017-02-24
期刊：
影响因子：
--
通讯作者：
Walsh K
中科院分区：
文献类型：
--
作者：
Fuster JJ;MacLauchlan S;Zuriaga MA;Polackal MN;Ostriker AC;Chakraborty R;Wu CL;Sano S;Muralidharan S;Rius C;Vuong J;Jacob S;Muralidhar V;Robertson AA;Cooper MA;Andrés V;Hirschi KK;Martin KA;Walsh K
人类衰老与造血细胞中体细胞突变频率的增加有关。这些复发性突变中的几个，包括编码表观遗传修饰酶TET 2的基因中的那些，促进突变血细胞的扩增。这种克隆性造血与动脉粥样硬化性心血管疾病的风险增加相关。我们研究了Tet 2突变细胞在动脉粥样硬化倾向、低密度脂蛋白受体缺陷（Ldlr−/−）小鼠中扩增的影响。我们发现用TET 2缺陷细胞进行部分骨髓重建足以使其克隆性扩增，并导致动脉粥样硬化斑块大小显著增加。TET 2缺陷型巨噬细胞表现出NLRP 3炎性小体介导的白细胞介素-1 β分泌增加。NLRP 3抑制剂在用TET 2缺陷细胞重建的嵌合小鼠中显示出比非嵌合小鼠更大的动脉粥样硬化保护活性。这些结果支持血细胞中的体细胞TET 2突变在动脉粥样硬化中起因果作用的假设。
Human aging is associated with an increased frequency of somatic mutations in hematopoietic cells. Several of these recurrent mutations, including those in the gene encoding the epigenetic modifier enzyme TET2, promote expansion of the mutant blood cells. This clonal hematopoiesis correlates with an increased risk of atherosclerotic cardiovascular disease. We studied the effects of the expansion of Tet2-mutant cells in atherosclerosis-prone, low-density lipoprotein receptor–deficient (Ldlr−/−) mice. We found that partial bone marrow reconstitution with TET2-deficient cells was sufficient for their clonal expansion and led to a marked increase in atherosclerotic plaque size. TET2-deficient macrophages exhibited an increase in NLRP3 inflammasome–mediated interleukin-1β secretion. An NLRP3 inhibitor showed greater atheroprotective activity in chimeric mice reconstituted with TET2-deficient cells than in nonchimeric mice. These results support the hypothesis that somatic TET2 mutations in blood cells play a causal role in atherosclerosis.
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影响因子：
30.8
作者：
Busque L;Patel JP;Figueroa ME;Vasanthakumar A;Provost S;Hamilou Z;Mollica L;Li J;Viale A;Heguy A;Hassimi M;Socci N;Bhatt PK;Gonen M;Mason CE;Melnick A;Godley LA;Brennan CW;Abdel-Wahab O;Levine RL
通讯作者：
Levine RL
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
8.8
作者：
McKerrell T;Park N;Moreno T;Grove CS;Ponstingl H;Stephens J;Understanding Society Scientific Group;Crawley C;Craig J;Scott MA;Hodkinson C;Baxter J;Rad R;Forsyth DR;Quail MA;Zeggini E;Ouwehand W;Varela I;Vassiliou GS
通讯作者：
Vassiliou GS
影响因子：
4
作者：
Vijg J
通讯作者：
Vijg J
影响因子：
30.8
作者：
Bonnefond, Amelie;Skrobek, Boris;Froguel, Philippe
通讯作者：
Froguel, Philippe