Macrophage-dependent IL-1 beta production induces cardiac arrhythmias in diabetic mice

Diabetes mellitus (DM) encompasses a multitude of secondary disorders, including heart disease. One of the most frequent and potentially life threatening disorders of DM-induced heart disease is ventricular tachycardia (VT). Here we show that toll-like receptor 2 (TLR2) and NLRP3 inflammasome activa...

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Detalles Bibliográficos
Autores: Monnerat, Gustavo, Alarcón, Micaela L., Vasconcellos, Luiz R., Hochman-Mendez, Camila, Brasil, Guilherme, Bassani, Rosana A., Casis Sáenz, Oscar, Malan, Daniela, Travassos, Leonardo H., Sepúlveda, Marisa, Burgos, Juan Ignacio, Vila Petroff, Martin, Dutra, Fabiano F., Bozza, Marcelo T., Paiva, Claudia N., Bastos Carvalho, Adriana, Bonomo, Adriana, Fleischmann, Bernd K., Campos de Carvalho, Antonio Carlos, Medei, Emiliano
Tipo de recurso: artículo
Fecha de publicación:2016
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/25728
Acceso en línea:http://hdl.handle.net/10810/25728
Access Level:acceso abierto
Palabra clave:toll-like receptors
NLRP3 inflammasome
sarcoplasmic-reticulum
ventricular repolarization
myocardial-infarction
insulin-resistance
NALP3 inflammasome
converting-enzyme
human monocytes
activation
Descripción
Sumario:Diabetes mellitus (DM) encompasses a multitude of secondary disorders, including heart disease. One of the most frequent and potentially life threatening disorders of DM-induced heart disease is ventricular tachycardia (VT). Here we show that toll-like receptor 2 (TLR2) and NLRP3 inflammasome activation in cardiac macrophages mediate the production of IL-1 beta in DM mice. IL-1 beta causes prolongation of the action potential duration, induces a decrease in potassium current and an increase in calcium sparks in cardiomyocytes, which are changes that underlie arrhythmia propensity. IL-1 beta-induced spontaneous contractile events are associated with CaMKII oxidation and phosphorylation. We further show that DM-induced arrhythmias can be successfully treated by inhibiting the IL-1 beta axis with either IL-1 receptor antagonist or by inhibiting the NLRP3 inflammasome. Our results establish IL-1 beta as an inflammatory connection between metabolic dysfunction and arrhythmias in DM.

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