title: Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.
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 ofTet2-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 somaticTET2mutations in blood cells play a causal role in atherosclerosis.
authors.affiliation: Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA. jjfuster@bu.edu kxwalsh@bu.edu.
authors.forename: José J
authors.identifier: 0000-0002-5970-629X
authors.initials: JJ
authors.lastname: Fuster
authors.affiliation: Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Susan
authors.identifier: 0000-0001-9689-0826
authors.initials: S
authors.lastname: MacLauchlan
authors.affiliation: Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: María A
authors.identifier: 0000-0003-0422-2965
authors.initials: MA
authors.lastname: Zuriaga
authors.affiliation: Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Maya N
authors.initials: MN
authors.lastname: Polackal
authors.affiliation: 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.
authors.forename: Allison C
authors.identifier: 0000-0002-2538-0818
authors.initials: AC
authors.lastname: Ostriker
authors.affiliation: 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.
authors.forename: Raja
authors.initials: R
authors.lastname: Chakraborty
authors.affiliation: Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Chia-Ling
authors.identifier: 0000-0002-5681-5140
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Soichi
authors.identifier: 0000-0003-2805-6252
authors.initials: S
authors.lastname: Sano
authors.affiliation: Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Muralidharan
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and CIBER de Enfermedades Cardiovasculares, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rius
authors.affiliation: Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Jacqueline
authors.identifier: 0000-0001-5903-2339
authors.initials: J
authors.lastname: Vuong
authors.affiliation: Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Sophia
authors.identifier: 0000-0001-6733-0184
authors.initials: S
authors.lastname: Jacob
authors.affiliation: Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Varsha
authors.initials: V
authors.lastname: Muralidhar
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Avril A B
authors.identifier: 0000-0002-9652-8357
authors.initials: AA
authors.lastname: Robertson
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) and CIBER de Enfermedades Cardiovasculares, Madrid, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Andrés
authors.affiliation: Yale Cardiovascular Research Center and Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06511, USA.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Hirschi
authors.affiliation: 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.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Martin
authors.affiliation: Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA. jjfuster@bu.edu kxwalsh@bu.edu.
authors.forename: Kenneth
authors.identifier: 0000-0001-7580-2276
authors.initials: K
authors.lastname: Walsh
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D058847:Inflammasomes / Q000378:metabolism; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011518:Proto-Oncogene Proteins; D011973:Receptors, LDL; D049308:Dioxygenases; C551914:Tet2 protein, mouse