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

MONNERAT, GUSTAVO; ALARCÓN, MICAELA L.; VASCONCELLOS, LUIZ R.; HOCHMAN-MENDEZ, CAMILA; BRASIL, GUILHERME; BASSANI, ROSANA A.; CASIS, OSCAR; MALAN, DANIELA; TRAVASSOS, LEONARDO H.; SEPÚLVEDA, MARISA; BURGOS, JUAN IGNACIO; VILA-PETROFF, MARTIN; DUTRA, FABIANO F.; BOZZA, MARCELO T.; PAIVA, CLAUDIA N.; CARVALHO, ADRIANA BASTOS; BONOMO, ADRIANA; FLEISCHMANN, BERND K.; DE CARVALHO, ANTONIO CARLOS CAMPOS; MEDEI, EMILIANO

NATURE COMMUNICATIONS

Nature Publishing Group

Lugar: Londres; Año: 2016 vol. 7

2041-1723

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.