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

Gustavo Monnerat, Micaela L. Alarcón, Luiz R. Vasconcellos, Camila Hochman-Mendez, Guilherme Brasil, Rosana A. Bassani, Oscar Casis, Daniela Malan, Leonardo H. Travassos, Marisa Sepúlveda, Juan Ignacio Burgos, Martin Vila-Petroff, Fabiano F. Dutra, Marcelo T. Bozza, Claudia N. Paiva, Adriana Bastos Carvalho, Adriana Bonomo, Bernd K. Fleischmann, Antonio Carlos Campos de Carvalho and Emiliano Medei ()
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Gustavo Monnerat: Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro
Micaela L. Alarcón: Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro
Luiz R. Vasconcellos: LIRS-Laboratory of Immunoreceptors and Signaling, Universidade Federal do Rio de Janeiro
Camila Hochman-Mendez: Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro
Guilherme Brasil: Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro
Rosana A. Bassani: Center for Biomedical Engineering, University of Campinas
Oscar Casis: Facultad de Farmacia, Universidad del País Vasco UPV/EHU
Daniela Malan: Institute of Physiology I, Life and Brain Center, University of Bonn
Leonardo H. Travassos: LIRS-Laboratory of Immunoreceptors and Signaling, Universidade Federal do Rio de Janeiro
Marisa Sepúlveda: Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata
Juan Ignacio Burgos: Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata
Martin Vila-Petroff: Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata
Fabiano F. Dutra: Instituto de Microbiologia, Universidade Federal do Rio de Janeiro
Marcelo T. Bozza: Instituto de Microbiologia, Universidade Federal do Rio de Janeiro
Claudia N. Paiva: Instituto de Microbiologia, Universidade Federal do Rio de Janeiro
Adriana Bastos Carvalho: Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro
Adriana Bonomo: Instituto de Microbiologia, Universidade Federal do Rio de Janeiro
Bernd K. Fleischmann: Institute of Physiology I, Life and Brain Center, University of Bonn
Antonio Carlos Campos de Carvalho: Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro
Emiliano Medei: Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13344

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