MiR-146a Regulates Neutrophil Extracellular Trap Formation That Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation

Atrial fibrillation (AF) patients experience adverse cardiovascular events (ACEs) despite anticoagulant therapy. We reported that rs2431697 of miR-146a, a negative regulator of inflammation, predicts ACEs in patients with AF. The relationship between neutrophil extracellular traps and thrombogenesis...

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Autores: Arroyo, Ana Belén, de los Reyes García, Ascensión M., Rivera Caravaca, José Miguel, Valledor, Patricia, García Barberá, Nuria, Roldán, Vanessa, Vicente, Vicente, Martínez, Constantino, González Conejero, Rocío
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universidad Católica San Antonio de Murcia (UCAM)
Repositorio:RIUCAM. Repositorio Institucional de la Universidad Católica San Antonio de Murcia
OAI Identifier:oai:repositorio.ucam.edu:10952/10687
Acceso en línea:http://hdl.handle.net/10952/10687
Access Level:acceso abierto
Palabra clave:Atrial fibrillation
Extracellular trap
Inflammation
MicroRNA
Neutrophil
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dc.title.none.fl_str_mv MiR-146a Regulates Neutrophil Extracellular Trap Formation That Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation
title MiR-146a Regulates Neutrophil Extracellular Trap Formation That Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation
spellingShingle MiR-146a Regulates Neutrophil Extracellular Trap Formation That Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation
Arroyo, Ana Belén
Atrial fibrillation
Extracellular trap
Inflammation
MicroRNA
Neutrophil
title_short MiR-146a Regulates Neutrophil Extracellular Trap Formation That Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation
title_full MiR-146a Regulates Neutrophil Extracellular Trap Formation That Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation
title_fullStr MiR-146a Regulates Neutrophil Extracellular Trap Formation That Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation
title_full_unstemmed MiR-146a Regulates Neutrophil Extracellular Trap Formation That Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation
title_sort MiR-146a Regulates Neutrophil Extracellular Trap Formation That Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation
dc.creator.none.fl_str_mv Arroyo, Ana Belén
de los Reyes García, Ascensión M.
Rivera Caravaca, José Miguel
Valledor, Patricia
García Barberá, Nuria
Roldán, Vanessa
Vicente, Vicente
Martínez, Constantino
González Conejero, Rocío
author Arroyo, Ana Belén
author_facet Arroyo, Ana Belén
de los Reyes García, Ascensión M.
Rivera Caravaca, José Miguel
Valledor, Patricia
García Barberá, Nuria
Roldán, Vanessa
Vicente, Vicente
Martínez, Constantino
González Conejero, Rocío
author_role author
author2 de los Reyes García, Ascensión M.
Rivera Caravaca, José Miguel
Valledor, Patricia
García Barberá, Nuria
Roldán, Vanessa
Vicente, Vicente
Martínez, Constantino
González Conejero, Rocío
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Atrial fibrillation
Extracellular trap
Inflammation
MicroRNA
Neutrophil
topic Atrial fibrillation
Extracellular trap
Inflammation
MicroRNA
Neutrophil
description Atrial fibrillation (AF) patients experience adverse cardiovascular events (ACEs) despite anticoagulant therapy. We reported that rs2431697 of miR-146a, a negative regulator of inflammation, predicts ACEs in patients with AF. The relationship between neutrophil extracellular traps and thrombogenesis is known. Thus, our aim was to evaluate the role of neutrophil extracellular trap compounds as prognostic markers of ACEs in AF and to study whether miR-146a affects NETosis. Approach and results: We included 336 steadily anticoagulated AF patients with a median follow-up of 7.9 years (interquartile range, 7.3-8.1) and 127 healthy subjects. The reviewed ACEs included stroke (ischemic/embolic), acute coronary syndrome, acute heart failure, and global or vascular death. We quantified cell-free DNA and NE (neutrophil elastase) at diagnosis. Rs2431697 was genotyped. Neutrophils from human and mice were seeded to analyze shed cell-free DNA and H3cit (citrullinated histone 3) after activation. In human plasmas, higher NE levels (>55.29 ng/mL), but not cell-free DNA, were independently associated with higher risk of all-cause mortality (hazard ratio, 2.24; 95% CI, 1.36-3.68), cardiovascular mortality (hazard ratio, 4.77; 95% CI, 1.11-20.47), and composite cardiovascular events (hazard ratio, 1.84; 95% CI, 1.01-3.76). In patients, NE levels were associated with rs2431697 (TT: 51.82±2.73 versus CC: 40.01±3.05 ng/mL; P=0.040). In vitro, both human (TT for rs2431697) and miR-146a-/- mice neutrophils yielded higher levels of cell-free DNA and H3cit than CC or wild-type cells, respectively. Conclusions: NE activity can provide new ACE prognostic information in AF patients. These findings provide evidence of a potential role of miR-146a in neutrophil extracellular trap generation and cardiovascular risk in AF.
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10952/10687
url http://hdl.handle.net/10952/10687
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:RIUCAM. Repositorio Institucional de la Universidad Católica San Antonio de Murcia
instname:Universidad Católica San Antonio de Murcia (UCAM)
instname_str Universidad Católica San Antonio de Murcia (UCAM)
reponame_str RIUCAM. Repositorio Institucional de la Universidad Católica San Antonio de Murcia
collection RIUCAM. Repositorio Institucional de la Universidad Católica San Antonio de Murcia
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling MiR-146a Regulates Neutrophil Extracellular Trap Formation That Predicts Adverse Cardiovascular Events in Patients With Atrial FibrillationArroyo, Ana Belénde los Reyes García, Ascensión M.Rivera Caravaca, José MiguelValledor, PatriciaGarcía Barberá, NuriaRoldán, VanessaVicente, VicenteMartínez, ConstantinoGonzález Conejero, RocíoAtrial fibrillationExtracellular trapInflammationMicroRNANeutrophilAtrial fibrillation (AF) patients experience adverse cardiovascular events (ACEs) despite anticoagulant therapy. We reported that rs2431697 of miR-146a, a negative regulator of inflammation, predicts ACEs in patients with AF. The relationship between neutrophil extracellular traps and thrombogenesis is known. Thus, our aim was to evaluate the role of neutrophil extracellular trap compounds as prognostic markers of ACEs in AF and to study whether miR-146a affects NETosis. Approach and results: We included 336 steadily anticoagulated AF patients with a median follow-up of 7.9 years (interquartile range, 7.3-8.1) and 127 healthy subjects. The reviewed ACEs included stroke (ischemic/embolic), acute coronary syndrome, acute heart failure, and global or vascular death. We quantified cell-free DNA and NE (neutrophil elastase) at diagnosis. Rs2431697 was genotyped. Neutrophils from human and mice were seeded to analyze shed cell-free DNA and H3cit (citrullinated histone 3) after activation. In human plasmas, higher NE levels (>55.29 ng/mL), but not cell-free DNA, were independently associated with higher risk of all-cause mortality (hazard ratio, 2.24; 95% CI, 1.36-3.68), cardiovascular mortality (hazard ratio, 4.77; 95% CI, 1.11-20.47), and composite cardiovascular events (hazard ratio, 1.84; 95% CI, 1.01-3.76). In patients, NE levels were associated with rs2431697 (TT: 51.82±2.73 versus CC: 40.01±3.05 ng/mL; P=0.040). In vitro, both human (TT for rs2431697) and miR-146a-/- mice neutrophils yielded higher levels of cell-free DNA and H3cit than CC or wild-type cells, respectively. Conclusions: NE activity can provide new ACE prognostic information in AF patients. These findings provide evidence of a potential role of miR-146a in neutrophil extracellular trap generation and cardiovascular risk in AF.Este estudio investiga la relación entre las trampas extracelulares de neutrófilos y el riesgo de eventos cardiovasculares adversos en pacientes con fibrilación auricular. La investigación destaca que los niveles plasmáticos elevados de elastasa neutrofílica, específicamente por encima de 55.29 ng/mL, funcionan como un biomarcador pronóstico independiente para la mortalidad por todas las causas, la mortalidad cardiovascular y los eventos cardiovasculares compuestos en pacientes anticoagulados. A diferencia del ADN libre de células, la elastasa neutrofílica demostró ser un marcador más específico y útil para predecir complicaciones a largo plazo. Un hallazgo fundamental del artículo es la descripción del mecanismo molecular donde el microARN-146a actúa como regulador de la formación de estas trampas, siendo el primer estudio en sugerir esta implicación. Los resultados indican que niveles bajos de este microARN, condicionados por el polimorfismo rs2431697, promueven una mayor formación de trampas extracelulares. Esta relación causal fue validada mediante modelos in vitro con neutrófilos humanos y en ratones que carecían de miR-146a, los cuales mostraron una liberación significativamente mayor de marcadores de NETosis. Desde una perspectiva de aplicación clínica, el estudio evaluó la integración de la elastasa neutrofílica en la escala de riesgo CHA2DS2-VASc. Se observó que la puntuación modificada mejoró la capacidad predictiva para la mortalidad y los eventos cardiovasculares. Asimismo, se logró una reclasificación positiva significativa de los pacientes en cuanto a su riesgo de mortalidad por todas las causas al añadir este biomarcador a la escala clínica estándar. En conclusión, el trabajo establece a la elastasa neutrofílica como una herramienta valiosa para la estratificación del riesgo y sugiere que el control genético de la inflamación a través de microARNs es clave en la patofisiología de las complicaciones en la fibrilación auricular.Medicina2018info:eu-repo/semantics/articlehttp://hdl.handle.net/10952/10687reponame:RIUCAM. Repositorio Institucional de la Universidad Católica San Antonio de Murciainstname:Universidad Católica San Antonio de Murcia (UCAM)Inglésinfo:eu-repo/semantics/openAccessoai:repositorio.ucam.edu:10952/106872026-06-07T18:35:21Z
score 15,81155

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