Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice

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...

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Detalles Bibliográficos
Autores: Fuster, José J, MacLauchlan, Susan, Zuriaga, María A, Polackal, Maya N, Ostriker, Allison C, Chakraborty, Raja, Wu, Chia-Ling, Sano, Soichi, Muralidharan, Sujatha, Rius, Cristina, Vuong, Jacqueline, Jacob, Sophia, Muralidhar, Varsha, Robertson, Avril A B, Cooper, Matthew A, Andres, Vicente, Hirschi, Karen K, Martin, Kathleen A, Walsh, Kenneth
Tipo de recurso: artículo
Fecha de publicación:2017
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/9683
Acceso en línea:http://hdl.handle.net/20.500.12105/9683
Access Level:acceso abierto
Palabra clave:Animals
Atherosclerosis
DNA-Binding Proteins
Hematopoiesis
Hematopoietic Stem Cells
Inflammasomes
Macrophages
Mice
Mice, Inbred C57BL
Mutation
NLR Family, Pyrin Domain-Containing 3 Protein
Plaque, Atherosclerotic
Proto-Oncogene Proteins
Receptors, LDL
Descripción
Sumario: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.

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