Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice

Science. 2017 Feb 24;355(6327):842-847. doi: 10.1126/science.aag1381. Epub 2017 Jan 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis / genetics*
  • DNA-Binding Proteins / genetics*
  • Hematopoiesis / genetics*
  • Hematopoietic Stem Cells / metabolism*
  • Inflammasomes / metabolism
  • Macrophages
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Plaque, Atherosclerotic / genetics
  • Proto-Oncogene Proteins / genetics*
  • Receptors, LDL / genetics

Substances

  • DNA-Binding Proteins
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Proto-Oncogene Proteins
  • Receptors, LDL
  • Tet2 protein, mouse