title: Macrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice.
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.
authors.affiliation: Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Monnerat
authors.affiliation: Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Micaela L
authors.initials: ML
authors.lastname: Alarcón
authors.affiliation: LIRS-Laboratory of Immunoreceptors and Signaling, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.|Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Luiz R
authors.initials: LR
authors.lastname: Vasconcellos
authors.affiliation: Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Camila
authors.initials: C
authors.lastname: Hochman-Mendez
authors.affiliation: Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Guilherme
authors.identifier: http://orcid.org/0000-0002-4695-4710
authors.initials: G
authors.lastname: Brasil
authors.affiliation: Center for Biomedical Engineering, University of Campinas, Campinas 13.083-970, Brazil.
authors.forename: Rosana A
authors.initials: RA
authors.lastname: Bassani
authors.affiliation: Departamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, 01006 Vitoria, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Casis
authors.affiliation: Institute of Physiology I, Life and Brain Center, University of Bonn, Bonn D-53127, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Malan
authors.affiliation: LIRS-Laboratory of Immunoreceptors and Signaling, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Leonardo H
authors.initials: LH
authors.lastname: Travassos
authors.affiliation: Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata 1900, Argentina.
authors.forename: Marisa
authors.initials: M
authors.lastname: Sepúlveda
authors.affiliation: Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata 1900, Argentina.
authors.forename: Juan Ignacio
authors.initials: JI
authors.lastname: Burgos
authors.affiliation: Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata 1900, Argentina.
authors.forename: Martin
authors.initials: M
authors.lastname: Vila-Petroff
authors.affiliation: Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Fabiano F
authors.initials: FF
authors.lastname: Dutra
authors.affiliation: Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Marcelo T
authors.initials: MT
authors.lastname: Bozza
authors.affiliation: Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Claudia N
authors.initials: CN
authors.lastname: Paiva
authors.affiliation: Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
authors.forename: Adriana Bastos
authors.initials: AB
authors.lastname: Carvalho
authors.affiliation: Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.|FIOCANCER/ VPPLR/FIOCRUZ, FIOCRUZ-Manguinhos, Rio de Janeiro 21040-360, Brazil.
authors.forename: Adriana
authors.initials: A
authors.lastname: Bonomo
authors.affiliation: Institute of Physiology I, Life and Brain Center, University of Bonn, Bonn D-53127, Germany.
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Fleischmann
authors.affiliation: Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.|National Center for Structural Biology and Bioimaging-CENABIO/UFRJ, Rio de Janeiro 21941-902, Brazil.
authors.forename: Antonio Carlos Campos
authors.initials: ACC
authors.lastname: de Carvalho
authors.affiliation: Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.|National Center for Structural Biology and Bioimaging-CENABIO/UFRJ, Rio de Janeiro 21941-902, Brazil.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Medei
mesh_terms: D000200:Action Potentials; D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D058847:Inflammasomes / Q000037:antagonists & inhibitors; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000276:immunology / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D011188:Potassium / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*
chemical_list: D018501:Antirheumatic Agents; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017472:Receptors, Interleukin-1; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C000628184:Casp1 protein, mouse; D020170:Caspase 1; D011188:Potassium; D002118:Calcium