RESUMEN
BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), a common age-associated phenomenon, associates with increased risk of both hematological malignancy and cardiovascular disease. Although CHIP is known to increase the risk of myocardial infarction and heart failure, the influence of CHIP in cardiac arrhythmias, such as atrial fibrillation (AF), is less explored. METHODS: CHIP prevalence was determined in the UK Biobank, and incident AF analysis was stratified by CHIP status and clone size using Cox proportional hazard models. Lethally irradiated mice were transplanted with hematopoietic-specific loss of Tet2, hematopoietic-specific loss of Tet2 and Nlrp3, or wild-type control and fed a Western diet, compounded with or without NLRP3 (NLR [NACHT, LRR {leucine rich repeat}] family pyrin domain containing protein 3) inhibitor, NP3-361, for 6 to 9 weeks. Mice underwent in vivo invasive electrophysiology studies and ex vivo optical mapping. Cardiomyocytes from Ldlr-/- mice with hematopoietic-specific loss of Tet2 or wild-type control and fed a Western diet were isolated to evaluate calcium signaling dynamics and analysis. Cocultures of pluripotent stem cell-derived atrial cardiomyocytes were incubated with Tet2-deficient bone marrow-derived macrophages, wild-type control, or cytokines IL-1ß (interleukin 1ß) or IL-6 (interleukin 6). RESULTS: Analysis of the UK Biobank showed individuals with CHIP, in particular TET2 CHIP, have increased incident AF. Hematopoietic-specific inactivation of Tet2 increases AF propensity in atherogenic and nonatherogenic mouse models and is associated with increased Nlrp3 expression and CaMKII (Ca2+/calmodulin-dependent protein kinase II) activation, with AF susceptibility prevented by inactivation of Nlrp3. Cardiomyocytes isolated from Ldlr-/- mice with hematopoietic inactivation of Tet2 and fed a Western diet have impaired calcium release from the sarcoplasmic reticulum into the cytosol, contributing to atrial arrhythmogenesis. Abnormal sarcoplasmic reticulum calcium release was recapitulated in cocultures of cardiomyocytes with the addition of Tet2-deficient macrophages or cytokines IL-1ß or IL-6. CONCLUSIONS: We identified a modest association between CHIP, particularly TET2 CHIP, and incident AF in the UK Biobank population. In a mouse model of AF resulting from hematopoietic-specific inactivation of Tet2, we propose altered calcium handling as an arrhythmogenic mechanism, dependent on Nlrp3 inflammasome activation. Our data are in keeping with previous studies of CHIP in cardiovascular disease, and further studies into the therapeutic potential of NLRP3 inhibition for individuals with TET2 CHIP may be warranted.
Asunto(s)
Fibrilación Atrial , Hematopoyesis Clonal , Proteínas de Unión al ADN , Dioxigenasas , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas Proto-Oncogénicas , Animales , Dioxigenasas/metabolismo , Dioxigenasas/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Fibrilación Atrial/metabolismo , Fibrilación Atrial/etiología , Fibrilación Atrial/genética , Fibrilación Atrial/patología , Inflamasomas/metabolismo , Humanos , Ratones , Hematopoyesis Clonal/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Masculino , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Anciano , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Persona de Mediana Edad , Ratones Noqueados , Factores de RiesgoRESUMEN
The ubiquitination of proteins by E3 ligases has become an important regulatory mechanism for a variety of immune functions, including the maintenance of self tolerance and suppression of autoreactive T cell development. This review highlights recent advances in our knowledge of the functions in this context of known and potential E3 ligases, including autoimmune regulator (AIRE), TNF receptor-associated factor 6 (TRAF6), Casitas B cell lymphoma b (Cbl-b), gene related to anergy in lymphocytes (GRAIL), Itch, and Roquin. We discuss how disruptions to these molecules may contribute to the loss of T cell homeostasis and the pathogenesis of autoimmunity. We also report on the implications of the potential coordinated actions of these molecules for T cell anergy and regulatory T cell (Treg) functions. The great diversity of E3 ligases and the growing list of cellular processes in which ubiquitination plays a role make for an exciting field of research. Findings emerging from these investigations may suggest ways to exploit the therapeutic potential of manipulating ubiquitination, particularly for autoimmune disorders.