Format

Send to

Choose Destination
See comment in PubMed Commons below
Science. 2017 Feb 24;355(6327):842-847. doi: 10.1126/science.aag1381. Epub 2017 Jan 19.

Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.

Author information

1
Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA. jjfuster@bu.edu kxwalsh@bu.edu.
2
Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
3
Yale Cardiovascular Research Center, Vascular Biology and Therapeutics Program, and Departments of Medicine and Pharmacology, Yale University School of Medicine, New Haven, CT 06511, USA.
4
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and CIBER de Enfermedades Cardiovasculares, Madrid, Spain.
5
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
6
Yale Cardiovascular Research Center and Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06511, USA.

Abstract

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.

PMID:
28104796
PMCID:
PMC5542057
DOI:
10.1126/science.aag1381
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center