Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice

被引：1113

作者：

Fuster, Jose J. ^{[1
]}

MacLauchlan, Susan ^{[1
]}

Zuriaga, Maria A. ^{[1
]}

Polackal, Maya N. ^{[1
]}

Ostriker, Allison C. ^{[2
,3
,4
]}

Chakraborty, Raja ^{[2
,3
,4
]}

Wu, Chia-Ling ^{[1
]}

Sano, Soichi ^{[1
]}

Muralidharan, Sujatha ^{[1
]}

Rius, Cristina ^{[5
,6
]}

Vuong, Jacqueline ^{[1
]}

Jacob, Sophia ^{[1
]}

Muralidhar, Varsha ^{[1
]}

Robertson, Avril A. B. ^{[7
]}

Cooper, Matthew A. ^{[7
]}

Andres, Vicente ^{[5
,6
]}

Hirschi, Karen K. ^{[8
,9
]}

Martin, Kathleen A. ^{[2
,3
,4
]}

Walsh, Kenneth ^{[1
]}

机构：

[1] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Mol Cardiol, Boston, MA 02118 USA

[2] Yale Univ, Sch Med, Yale Cardiovasc Res Ctr, Vasc Biol & Therapeut Program, 333 Cedar St, New Haven, CT 06511 USA

[3] Yale Univ, Sch Med, Dept Med, 333 Cedar St, New Haven, CT 06511 USA

[4] Yale Univ, Sch Med, Dept Pharmacol, 333 Cedar St, New Haven, CT 06511 USA

[5] Ctr Nacl Invest Cardiovasc Carlos III CNIC, Madrid, Spain

[6] CIBER Enfermedades Cardiovasc, Madrid, Spain

[7] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[8] Yale Univ, Sch Med, Yale Cardiovasc Res Ctr, 333 Cedar St, New Haven, CT 06511 USA

[9] Yale Univ, Sch Med, Yale Stem Cell Ctr, 333 Cedar St, New Haven, CT 06511 USA

来源：

SCIENCE | 2017年 / 355卷 / 6327期

关键词：

SUBCLINICAL ATHEROSCLEROSIS; SOMATIC MUTATIONS; MYELOID CANCERS; RISK-FACTORS; STEM-CELLS; DIFFERENTIATION; MALIGNANCIES; HOMEOSTASIS; PREVALENCE; MOSAICISM;

D O I：

10.1126/science.aag1381

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-1b 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.

引用

页码：842 / 847

页数：6

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