Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome.
Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome.
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DOI：
10.1016/j.jacc.2017.12.037
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发表时间：
2018-02-27
影响因子：
24
通讯作者：
Walsh K
中科院分区：
文献类型：
--
作者：
Sano S;Oshima K;Wang Y;MacLauchlan S;Katanasaka Y;Sano M;Zuriaga MA;Yoshiyama M;Goukassian D;Cooper MA;Fuster JJ;Walsh K
最近的研究表明，由于白血病相关基因的体细胞突变，造血干细胞可以进行克隆扩增，导致血液中突变白细胞的年龄依赖性积累。这种体细胞突变相关的克隆性造血在健康老年人中很常见，但它与未来心血管疾病的发病率增加有关。表观遗传调节因子TET 2经常在表现出克隆造血的个体的血细胞中突变。在这里，我们研究了造血细胞内的Tet 2突变是否会导致两种心脏损伤模型的心力衰竭。通过横向主动脉缩窄或永久性结扎左前降支动脉引起的慢性缺血，通过压力超负荷诱导小鼠心力衰竭。使用Tet 2缺陷细胞的竞争性骨髓移植策略来模拟TET 2突变驱动的克隆造血。或者，使用从LysM启动子表达的Cre重组酶在骨髓细胞中特异性消融Tet 2。在两种实验性心力衰竭模型中，造血或骨髓Tet 2缺乏使心脏重塑和功能恶化，同时IL-1β表达增加。用选择性NLRP 3炎性体抑制剂治疗可以防止心力衰竭的发展，并消除Tet 2缺陷小鼠和野生型小鼠之间心脏参数的差异。造血细胞中Tet 2缺陷与心力衰竭小鼠模型中由于IL-1β信号传导升高而导致的更严重的心功能障碍相关。这些数据表明，具有TET 2介导的克隆造血的个体可能处于更大的发展心力衰竭的风险中，并且对IL-1β/NLRP 3炎性体抑制的反应更好。
Recent studies have shown that hematopoietic stem cells can undergo clonal expansion due to somatic mutations in leukemia-related genes, leading to an age-dependent accumulation of mutant leukocytes in the blood. This somatic mutation-related clonal hematopoiesis is common in the healthy elderly, but it has been associated with an increased incidence of future cardiovascular disease. The epigenetic regulator TET2 is frequently mutated in blood cells of individuals exhibiting clonal hematopoiesis. Here, we investigated whether Tet2 mutations within hematopoietic cells can contribute to heart failure in two models of cardiac injury. Heart failure was induced in mice by pressure overload, achieved by transverse aortic constriction or chronic ischemia induced by the permanent ligation of the left anterior descending artery. Competitive bone marrow transplantation strategies with Tet2-deficient cells were used to mimic TET2 mutation-driven clonal hematopoiesis. Alternatively, Tet2 was specifically ablated in myeloid cells using Cre recombinase expressed from the LysM promoter. In both experimental heart failure models, hematopoietic or myeloid Tet2 deficiency worsened cardiac remodeling and function, in parallel with increased IL-1β expression. Treatment with a selective NLRP3 inflammasome inhibitor protected against the development of heart failure and eliminated the differences in cardiac parameters between Tet2-deficient and wild-type mice. Tet2 deficiency in hematopoietic cells is associated with greater cardiac dysfunction in murine models of heart failure due to elevated IL-1β signaling. These data suggest that individuals with TET2-mediated clonal hematopoiesis may be at greater risk of developing heart failure and respond better to IL-1β/NLRP3 inflammasome inhibition.
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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：
9.8
作者：
Acuna-Hidalgo, Rocio;Sengul, Hilal;Hoischen, Alexander
通讯作者：
Hoischen, Alexander
影响因子：
8.3
作者：
Izumiya, Y;Shiojima, I;Walsh, K
通讯作者：
Walsh, K