Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome
S Sano, K Oshima, Y Wang, S MacLauchlan… - Journal of the American …, 2018 - jacc.org
S Sano, K Oshima, Y Wang, S MacLauchlan, Y Katanasaka, M Sano, MA Zuriaga…
Journal of the American College of Cardiology, 2018•jacc.orgBackground: Recent studies have shown that hematopoietic stem cells can undergo clonal
expansion secondary to somatic mutations in leukemia-related genes, thus leading to an
age-dependent accumulation of mutant leukocytes in the blood. This somatic mutation-
related clonal hematopoiesis is common in healthy older individuals, but it has been
associated with an increased incidence of future cardiovascular disease. The epigenetic
regulator TET2 is frequently mutated in blood cells of individuals exhibiting clonal …
expansion secondary to somatic mutations in leukemia-related genes, thus leading to an
age-dependent accumulation of mutant leukocytes in the blood. This somatic mutation-
related clonal hematopoiesis is common in healthy older individuals, but it has been
associated with an increased incidence of future cardiovascular disease. The epigenetic
regulator TET2 is frequently mutated in blood cells of individuals exhibiting clonal …
Background
Recent studies have shown that hematopoietic stem cells can undergo clonal expansion secondary to somatic mutations in leukemia-related genes, thus leading to an age-dependent accumulation of mutant leukocytes in the blood. This somatic mutation-related clonal hematopoiesis is common in healthy older individuals, but it has been associated with an increased incidence of future cardiovascular disease. The epigenetic regulator TET2 is frequently mutated in blood cells of individuals exhibiting clonal hematopoiesis.
Objectives
This study investigated whether Tet2 mutations within hematopoietic cells can contribute to heart failure in 2 models of cardiac injury.
Methods
Heart failure was induced in mice by pressure overload, achieved by transverse aortic constriction or chronic ischemia induced by the permanent ligation of the left anterior descending artery. Competitive bone marrow transplantation strategies with Tet2-deficient cells were used to mimic TET2 mutation-driven clonal hematopoiesis. Alternatively, Tet2 was specifically ablated in myeloid cells using Cre recombinase expressed from the LysM promoter.
Results
In both experimental heart failure models, hematopoietic or myeloid Tet2 deficiency worsened cardiac remodeling and function, in parallel with increased interleukin-1beta (IL-1β) expression. Treatment with a selective NLRP3 inflammasome inhibitor protected against the development of heart failure and eliminated the differences in cardiac parameters between Tet2-deficient and wild-type mice.
Conclusions
Tet2 deficiency in hematopoietic cells is associated with greater cardiac dysfunction in murine models of heart failure as a result of elevated IL-1β signaling. These data suggest that individuals with TET2-mediated clonal hematopoiesis may be at greater risk of developing heart failure and respond better to IL-1β–NLRP3 inflammasome inhibition.
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