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

2016; Nature Portfolio; Volume: 7; Issue: 1 Linguagem: Inglês

10.1038/ncomms13344

2041-1723

Gustavo Monnerat, Micaela López Alarcón, Luiz Ricardo C. Vasconcellos, Camila Hochman‐Mendez, Guilherme Visconde Brasil, Rosana A. Bassani, Óscar Casis, Daniela Malan, Leonardo H. Travassos, Marisa Sepúlveda, Juan Ignacio Burgos, Martín Vila Petroff, Fabiano Ferreira, Marcelo T. Bozza, Cláudia N. Paiva, Adriana Bastos Carvalho, Adriana Bonomo, Bernd K. Fleischmann, Antônio Carlos Campos de Carvalho, Emiliano Medei,

Ion Channels and Receptors

Abstract 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-1β in DM mice. IL-1β 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-1β-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-1β axis with either IL-1 receptor antagonist or by inhibiting the NLRP3 inflammasome. Our results establish IL-1β as an inflammatory connection between metabolic dysfunction and arrhythmias in DM.